JPH01268639A - Blood pressure regulation agent - Google Patents

Abstract

PURPOSE:To obtain a safe blood pressure regulation agent having excellent blood pressure increasing action as well as decreasing action, free from side effects such as hemolytic action and tachycardia and having high preservability or storability, by using dried powder of earthworm as an active component. CONSTITUTION:Living earthworm is (1) left in fresh water or an aqueous solution containing <=0.3wt.% of an organic acid, inorganic acid, their Na salt and/or K salt to discharge the feces in the digestive tracts and (2) washed with water to remove the filthy material attached to the surface of the body. As an alternative, living earth worm cleaned by the treatment (1) is subjected to the treatment (2). The treated body is subjected to set crushing and the resultant suspension is frozen at -10--60 deg.C and then dried in vacuum in frozen state for 10-100hr at -60-80 deg.C in a vacuum of <=10mmHg while intermittently raising the temperature. The vacuum drying of the final stage is carried out at 70-80 deg.C in a vacuum of 0.01-0.5mmHg for 5-10hr to obtain aseptic dried powder of earthworm having the above effect and useful as an active component for a blood pressure regulation agent in high yield.

Description

[Detailed description of the invention]

Industrial application field: The present invention relates to a blood pressure regulator or a hypertensive and hypotensive drug. More specifically, a blood pressure regulator that has excellent anti-hypertensive and/or anti-hypotensive effects and safety, and contains pharmacologically acceptable dried earthworm powder produced by a novel and innovative improved manufacturing method as an active ingredient. Or related to antihypertensive effect. Conventional technology: In recent years, there are many patients with high blood pressure or low blood pressure, regardless of their survival. To treat these patients, those with high blood pressure are often given antihypertensive drugs, and those with low blood pressure are often, but not always, given antihypertensive drugs (or vasopressors). . In recent years, with the increase in the number of hypertensive patients, various antihypertensive agents (or antihypertensive agents) have been developed and used. For hypertensive patients, after starting to take antihypertensive drugs σ),
If you stop taking it, your condition may worsen and become more severe. Therefore, it is often necessary to take drugs for long periods of time.When patients with hypotension also use drugs, they are often administered for long periods of time.Therefore, it is desirable to have drugs that have no side effects. For example, hydralazine, which is known as an antihypertensive agent, has a peripheral vasodilatory effect and has an excellent antihypertensive effect, but it causes tachycardia as a side effect, so it cannot be combined with β-blockers. In general, antihypertensive agents and antihypertensive agents are administered over a long period of time, so drugs with no side effects are especially desired.On the other hand, earthworms have been used since ancient times, mainly in oriental countries. It has been called a dragon and has been used as a medicine.The pharmacology and medicinal effects of earthworms reported in conventional literature are shown below.■ "Earths and Life" written by Shinryu Obuchi, 1947ff, Akihabara

[1
22) October 30th, published by Maki Shobo, No. 223-226
Pages and “Fukukuri Mizu” written by Shinkiji Hatai April 30, 1980
Published by Scientist Co., Ltd., No. 160-16
On page 3, earthworms are used to reduce bladder stones and excrete them from the body, to treat yellow pox, tonics, tonics, hair herbal medicines,
It has the pharmacological effects of tonic and antipyretic, while as earthworm poison, one affects the nervous system and the other destroys red blood cells, i.e.
It has been reported that it has hemolytic effects. ■ [The Dictionary of the People's Republic of China] Edited by the Dictionary Committee of the Ministry of Health of the People's Republic of China, 1977 edition, pages 197-198 of some ports states the following. Traditionally, there are two types of earth dragon products. That one wide area f
a (Lumbricus Kwangtungeai
a) Rip open the abdomen, wash away the internal organs and mud, and expose it to the sun.
Dry in the shade or at low temperatures. Other land dragons (i
, umbricus Nativus) are killed by placing them in plant ash, then removing the ash and drying them in the sun, shade, or at low temperatures, and the earthworm's body is filled with mud. It has been reported that these two types of earth dragons are used as an antipyretic, convulsion treatment, blood circulation promoter, hemiplegia treatment, joint analgesic, urinary agent, bronchial asthma agent, and hypertension agent. There is. () [Our Chinese Herbal Medicine Series 3, Earth Dragon Φ Squid Bone,
Chinese Scientific Research J October 30, 191, published by Matsuura Pharmaceutical Co., Ltd., page 7 reports that Earth Dragon tincture (ethyl alcohol extract of Earth Dragon) has a hypotensive effect. ■ "Dictionary of Natural Medicines" by Takuo Okuda, April 1, 1988
Published by Koyo Shoten on the 5th, page 215 states that the earth dragon is a hypothermic agent,
It has been reported that it is used as an analgesic, diuretic, and antidote. ■ Mamoru Tanaka [Hokkaido Medical Journal Vol. 24, pp. 18-24 (1949)] extracted the dried sludge with boiled water and added ethyl to the concentrated solution of this extract. The precipitated material obtained by adding alcohol (,[,t+mbro
It has been reported that when febrin) was dissolved in linogel solution and this solution was injected intravenously into anesthetized cats, there was a rapid drop in blood pressure, and an acceleration of blood coagulation was observed in proportion to the pain. . ■Kenji Iyou [Yamaguchi Igaku Vol. 9, pp. 571-576 (1960)] describes a physiological saline extract of Jiryu, ethyl alurur or acetone dried extract of Jiryu, dissolved in physiological saline [dissolved]. When the solution was intravenously injected into adult rabbits, a drop in blood pressure was observed. ■ Volume 2 of "Zhongkoma Dictionary", edited by Jiangsu New Medical College, published by Shanghai Science and Technology Publishing House, 1980, page 2112, contains wide stratum tincture, new dry powder suspension, and reed solution soaked in hot water of pregnant octopus. When a decoction of Shinko, etc. was administered to anesthetized dogs, large rats, cats, or mice with chronic renal hypertension, a slow and sustained hypotensive effect was observed. When the stratum extract was intravenously injected into anesthetized dogs or cats, a blood pressure lowering effect appeared rapidly. However, it has been reported that it was not effective when administered orally or when applied clinically. Furthermore, on page 2114 of the same magazine, the geological tincture with a concentration of 40 t (4 t of geodragon soaked in 60% ethyl alcohol 100%) is applied 3 times every 10-1-day [i.e., 1 t of geological formation 1129/day] equivalent (converted by the inventor)]. Those who cannot drink tinctures can make pills by adding water to pure geological powder (adding a small amount of excipients) and taking 3 to 4 f each time - 3 times a day [equivalent to Earth Dragon 9 to 1211 days]. If the inventor takes this drug and continues to take it for 30 to 60 days, it is effective against essential hypertension. Also, Earth Dragon B+
Q (Hyboxanthin was removed using Hgclz and the blood pressure lowering component was separated and extracted using an ion exchange resin) 2 - (including the herbal medicine Jiryu 8v) every -3 days.
It is reported that it was effective in treating essential hypertension when taken in doses [equivalent to 242 layers per day (calculated by the inventor)]. Conventional and customary methods for producing dried earthworm products or dry powder can be broadly classified as follows. ■ Open the abdomen of the earthworm to reveal its internal contents (viscera and mud)
A method of removing and drying in the sun, shade, or at low temperatures (usually below 50°C). ■ A method of killing earthworms by placing them in plant ash, removing the ash, and drying them in the sun, shade, or at low temperatures (usually below 50°C) to obtain earthworms with mud still stuck inside their bodies. ■ After removing the mud inside the earthworm's body, the earthworm is placed in plant ash or fire and dried. These dried products were pulverized and used when needed or used. These manufacturing methods are simple and economical, and have the advantage of being easily carried out at home. However, the dried earthworms or powder obtained by these methods should be stored in a refrigerator at 0 to 5°C.
Alternatively, mold may develop within a short period of about 6 months when stored in an open state at a room temperature of 5 to 45 C, and within a year when stored in a closed state, resulting in the product becoming unusable. Earthworms that have been dried with their bodies filled with mud, as in the production method (①) above, or earthworms that have been dried in plant ashes or fire, as in the [Ao] production method, are almost always treated with hot water when used as medicine. It is often extracted with water or decocted with boiled water, filtered, and taken as P solution. In particular, dried earthworm products or dried powder produced by the method (2) are rarely taken as earthworm tincture or powder, or in the form of pills. In addition to taking the earthworms produced by method ① as a hot water soak or decoction, they can also be taken as Jiryu tincture or Jiryu powder, or as a pill by adding a small amount of water or a small amount of excipient to the powder. There are many. When using the manufacturing method of ■ and [phase], moisture from raw earthworms is 1
The yield of dry earthworms from 0 to 16% is 5 to 19%. Recently, one of the inventors of the present invention, Yo Ishii, has developed a health food containing earthworm proteins and lipids as main components and a method for producing the same [Japanese Patent Application Publication No. 1983-216572 (publication date 1).
December 6, 984). This production is an excellent method for obtaining dried earthworm powder as a health food. However, it was found that the method for producing dried earthworm powder for medicinal uses such as arteriosclerotic agents (also known as antihyperlipidemic agents), antidiabetic agents, and blood pressure regulators was insufficient in terms of medicinal efficacy. That is, when applying an external action to remove excrement remaining in the living body of a living earthworm, it is not possible to selectively remove only the excrement. It has been found that no matter how careful the procedure is, the medicinal efficacy will be insufficient because the internal organs and body fluids, which contain many components that play an important role in medicinal efficacy, are removed along with the fecal soil. Moreover, the yield for raw earthworms is as low as 10 to 19 inches. Furthermore, a big problem is that the vacuum drying in the final finishing process is carried out at 80℃ and 0.3℃.
It has been found that the enzymes in the dried earthworm powder, which have important pharmacological and medicinal effects, are destroyed or inactivated due to long-term operation of 20 hours or more at a high vacuum level. Therefore, compared to the dried earthworm powder obtained by the production method of the present invention, the medicinal efficacy of the high surface pressure therapeutic agent of the dried earthworm powder obtained in Japanese Patent Application Publication No. 1982-216572 is about 50%. there were. Recently, Tsune Mihara, one of the inventors of the present invention, and other co-researchers have discovered that the fibrinolytic active substance of earthworms has an optimal pH of 8 to 1.
0, stable pH 5-10, inhibited by Trasylol (trade name), Transamine (trade name), soybean trypsin inhibitor and serum, has plasminogen activation effect and fi7'lJ7 dissolution effect, and fibrinogen dissolution It was confirmed that this enzyme protein possesses various properties without any action. Patent application for a method for producing a fibrinolytic active substance consisting of a crude enzyme protein fraction extracted from earthworms using an aqueous solvent and a saccharide enzyme protein fraction obtained by purification thereof; (filed on February 27, 1982) and a foreign application claiming priority thereto, U.S. Patent Application No. 470394 (filed on February 28, 1983).
), UK patent application No. 8305359 (filing date 1
February 25, 983), Italian patent application A47795
A (filing date February 25, 1983), French patent application BI 03165 (filing date February 25, 1983), West German patent application AP 3306944.1 (filing date 19
February 28, 1983) and Canadian patent application A422034
(filing date February 21, 1983) is reported. Furthermore, Tsune Mihara et al. discovered six new species of bu a from earthworms.
Application for substance patent for Tease, namely, Japanese Patent Application Publication No. 1984-63i84 (filing date, 1982)
)$1O, September 2) and a patent application for a thrombolytic agent containing these prothiases as active ingredients, namely, Japanese Patent Application Publication No. 1841.31/1989 (filing date, Showa 58 (1)
983)) and the foreign patent application claiming priority of these combined applications, namely Korean Patent Application No. 2990 (
The following patent applications are reported as CAU (filing date: June 30, 1983). P, App, 16293 (filing date June 27, 1983), CA, P, App, 431387 (filing date 19
June 28, 1983), D″, P, App, 3008
(filing date June 29, 1983), EP, P, App.
, 83106288.0 (filing date June 2, 1983)
8th), ES, P, App, 523754 (filing date 1
June 30, 983), Fl, P, App. No. 832383 (filed June 29, 1983). P, App, 2399 (filing date June 30, 1983)
), PH, P, App, 29151 (filing date 19
June 30, 1983), TW, P, App, 721198
3 (filing date June 18, 1983), US, P, Ap
p. 508163 (filing date June 27, 1983)]
has been done. According to the research results of the present inventors, we could not find any literature reporting the activity of antihypotensive agents containing Ligo, Jiryu, and Earthworm dry powder as active ingredients. Furthermore, we have found all the literature that reports on the blood pressure regulating effect of dried earthworm powder, such as when administering dried earthworm powder to a patient with high blood pressure and/or hypotension, it brings the patient's systolic and diastolic blood pressure to normal values. I couldn't do it. Problems to be solved by the invention: Antihypertensive agents and antihypertensive agents are considered to be drugs that act independently. That is, since antihypertensive agents have the effect of lowering blood pressure, and antihypertensive agents have the effect of increasing blood pressure, they must always be taken under the supervision of a specialist doctor. For example, in the case of antihypertensive drugs, when a certain level of antihypertensive effect is confirmed, measures are taken such as changing the type of drug or stopping the drug depending on the stage. again,
If an increase in blood pressure occurs, the corresponding medication must be resumed. One drug can reduce high blood pressure and/or
Or it would be desirable to be able to cure hypotensive patients. That is, there is a need for a drug that brings the systolic and diastolic blood pressures of hypertensive and/or hypotensive patients to normal values. Furthermore, since this antihypertensive agent requires long-term administration, there is a particular need for a drug that is safe and has no side effects. Therefore, the present inventors have been conducting intensive research for many years with the aim of creating highly safe pharmaceuticals free of side effects from natural herbal medicines. As shown in the above-mentioned prior literature, it is known that dried earthworms have a blood pressure lowering effect. However, the yield of dried earthworms using classical conventional techniques is not only low at 5-19% compared to live earthworms, but even when stored in a sealed state at room temperature of 5-45°C, mold grows within a year. or deterioration, making it unsuitable for medicinal use. Alternatively, the enzymes in the dried earthworms may be destroyed or inactivated, resulting in insufficient or insufficient medicinal efficacy or side effects. Therefore, the present invention does not destroy or deactivate enzymes in dried earthworms, and has no side effects such as destruction of red blood cells, i.e., hemolysis, and tachycardia, and is highly safe.
Moreover, detailed studies have been carried out to obtain a high yield of sterile earthworm dry powder that can be stored or stored for at least 4 years under closed conditions. Measures to solve the problem: An improved manufacturing method was established. Manufacturing method 1. : Boiling earthworms with fresh water or organic acids such as acetic acid, citric acid, co-phosphoric acid, malic acid, tartaric acid, lactic acid, or phosphoric acid, sulfuric acid, etc.
At least one compound of an inorganic acid such as hydrochloric acid or a sodium or potassium salt of these acids at a low concentration of Th0.3 (weight) S or less, preferably 0.1 (weight) Th or less, or pH 3 to 6.5 in a slightly acidic aqueous solution at a temperature of 1
~25°C for 0.5--72 hours, preferably at temperature 2
Leave at ~15°C for 1 to 40 hours to fully excrete the fecal soil in the digestive tract of the live earthworms using the excretory power of the live earthworms themselves, then wash off the dirt adhering to the body surface of the live earthworms with water and apply a wet method. I did the pulverization. Wet-milled earthworms are kept at a low temperature below 15c.
! After freezing at a low temperature of -10 to -60C, freezing and vacuum drying were performed. The conditions for freezing and air drying are -60~+90℃, vacuum level below 100mrrf-1g, preferably -40~+80℃, vacuum level below 30rrITHg, and preferably for 5~100 hours while increasing the temperature step by step. Freeze and vacuum dry for 10 to 60 hours to obtain sterile dry earthworm powder. Manufacturing method 2. : After washing off the dirt adhering to the body surface of the living earthworm with water, wash it with fresh water or with organic acids such as acetic acid, citric acid, succinic acid, malic acid, tartaric acid, and lactic acid, or with inorganic acids such as phosphoric acid, sulfuric acid, and hydrochloric acid. A low concentration containing less than 0.3 (by weight) of one kind of acid or a sodium or potassium salt of an acid, preferably less than 0.1 (by weight), or a pH of 3 to 6. In a slightly acidic aqueous solution of .5 degrees,
At 25C, 0.5 to 72 hours, preferably m degrees 2 to 72 hours.
After leaving it for ~40 hours and sufficiently excreting the excretory soil in the digestive tract of the live earthworms using the excretory power of the live earthworms themselves, wet pulverization was performed. Wet-milled earthworms are heated at a low temperature of -15C or lower, preferably -10 to -
After freezing at a low temperature of 60° C., freezing and vacuum drying were performed. The conditions for this freezing/vacuum drying are -60 to +
900. Degree of vacuum 100 mmHg or less, preferably -4
0 to +80°C, 5 to 100 hours while increasing the temperature stepwise at a vacuum level of 3 Q +rnlHg or less, preferably 1
Freezing and vacuum drying were performed for 0 to 60 hours to obtain a sterile dry powder of earthworms. The wet grinding method of earthworms, that is, the method of destroying earthworm tissues (cells), involves making a suspension or homogeneous liquid using equipment such as a homogenizer, blender, homomixer, crusher, or pressurized cell destruction device. is preferred. The temperature during this wet pulverization is desirably 1 to 25C, preferably 2 to 15C. By the above procedure, it was possible to obtain tan or brown dry earthworm powder from living earthworms at a yield of 2 to 35 tons. Normally, the moisture content of this dry earthworm powder is 5-16%.
Preferably 7-14%, ash content 3-8t, preferably 4
The content of nitrogen was 1 to 11%, preferably 6 to 11%. In addition, the earthworm dry powder contains 18 types of aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, cysteine, valine, methionine, inleucine, leucine, tyrosine, phenylalanine, tryptophan, lysine, histidine, and arginine. Contains the amino acids before and after. Test Example 1 The above manufacturing method 1. and 2. Dry earthworm powder σ obtained by method
) The crude analysis results are shown in Table-1. Table-1 Test Example 2 M-2 and M- of earthworm dry powder products obtained by the manufacturing method
4 and manufacturing method 2. Earthworm dry powder product M-5 obtained by method
The component results are shown in Table 2. Table-2 Test Example 3 Manufacturing method 1. Amino acid analysis of the crude protein in the dry earthworm powder products of M-2 and M-4 obtained by the method 2 and M-5 obtained by the method 2 was carried out, and the analytical values of the protein foods fishmeal and soybean flour were analyzed. The results of comparison are shown in Table 3. Table-3 P, McDonald, R, A, Edwards
and J, F, D. Greenhalgh: Animal Nutri
According to Tables 2 and 3 from the data described in tion (1973), the dried earthworm powder obtained by production methods 1 and 2 contains abundant crude protein, crude lipids, and various metals. It was found that the amino acid composition of the crude protein contained a large amount of essential amino acids. Production method 1 yielded a slightly more preferable product than the dried earthworm powder obtained using production method 2. Furthermore, it is better to leave live earthworms in an aqueous solution containing at least one compound of the above-mentioned organic acids or inorganic acids or the sodium or potassium salts of both at the above-mentioned low concentration than to leave them in fresh water. The excretion of feces in the digestive tract of live earthworms is faster than that of live earthworms.
And the excretion rate is high. Tsune Mihara et al. [Japanese Patent Application Publication Publication No. 59-63184
No. 59-184131] fractionated six new proteases, which are fibrinolytic enzymes, from earthworms. Namely, Tsune Mihara et al.
) After carrying out ammonium sulfate fractionation on the supernatant liquid,
The precipitate was subjected to gel filtration using 5ephacryl S-residue 200, and the resulting protein fraction was DEAE-
As a result of cellulose ion exchange chromatography, it was found that it has casein-degrading and fibrin-degrading activity.
, ■ fraction protein was obtained. This summer, we will update about the fractions of ■ and ■.
-75, Toyopearl WH55, A CH-5epha
rose, Benzamidine-5epha
As a result of purification using rose etc., 6 fractions of purified enzyme were obtained. When molecular weight was measured by 5DS-PAGE, the molecular weight of fraction 1-00 was the lowest, calculated as 23,500, and then sequentially 1-111-2, ■, fil-
The molecular weight increases to 1,■-2, and 111-2 has a molecular weight of 34
,200. Furthermore, when the isoelectric points of these 6 fractions were measured by isoelectric focusing, I-0 was the highest at pH 4.12, and then the pH gradually decreased until it reached pH 3 at It-2.
, 52. These 6 fractions are new proteolytic enzymes that are different from serine enzymes, and the optimal pH of the proteases in these 6 fractions is around 8 or between pH 8 and 10.
It is reported that the stable pH was 4-12 or 5-12, and the optimum temperature was 50°C or 50-60C1 inactivation conditions were 70°C for 60 minutes. Dry earthworm powder product M-4 obtained by the above production methods 1 and 2
When 10 times the volume of physiological saline was added to M-5 and the supernatant was measured using a standard fibrin plate, fibrinolytic activity was immediately observed as shown in Table 4. When this M-4 earthworm dry powder was incubated in a physiological saline solution 'f: 37C, the fibrinolytic activity of the supernatant increased by about 4 times on the 10th day, as shown in Table 4. 5 times on the day, 75
It becomes 5.5 times on the first day. This fact suggests that a large amount of the precursor of this protease exists in the freeze-dried earthworm powder, and the enzyme activity is expressed through autolysis. When the activity of the supernatant on day 50 is converted into international units of urokinase and compared, it is approximately s, oo. It was calculated as IU/mt. In addition, this enzyme dissolves in plasminogen-free V-purine plates and standard V-purin plates, and in the case of standard fibrin plates, plasminogen-free
The lysis window was larger than that of the free plate, and enzyme activity that directly degrades fibrin as well as plasminogen activator activity was exhibited. In the above procedure, the same results as shown in Table 4 were obtained using KM-5 earthworm dry powder instead of M-4. Table 4: Fibrinolytic activity of the supernatant obtained by adding 10 times the amount of physiological saline to the dried earthworm powder of the present invention and incubating it at 37C. Although the detailed reason for the blood pressure regulating effect, that is, antihypertensive effect and/or antihypertensive effect when orally administered to rats and humans (the same meaning hereinafter) is unknown, The proteolytic enzyme (protein) itself contained in earthworm dry powder or the precursor of this enzyme (
This is thought to be due to the effects of proteins themselves, proteins, lipids, or other unknown compounds, or their combination. It has a blood pressure regulating agent or antihypertensive effect of 10, ie, a crude protein content of 43.8 to 62.5%. Next, preferred specific examples of freezing and vacuum drying operations of the suspension obtained by wet pulverization of earthworms obtained by the above-mentioned Production Methods 1 and 2 are as follows. Wet-ground earthworms, i.e., earthworm suspensions, at -1
5 to 60 at 0 to -60°C, preferably -30 to -500
0.01-0.2 rrm at the same temperature after freezing for an hour
Lyophilize under vacuum at 1-1 g for 5-12 hours. Then at 20-30℃ for 5-15 hours, 0.01-0.2 mm
Dry under vacuum at 35-50°C, 0,1
Dry under vacuum at ~0.5 rrmHg for 10-20 hours. The next final finishing step, vacuum drying, is o, o i~0
, 5 rrmHg vacuum, 70-80°C, preferably 75
Vacuum drying at ~80°C for 5~10 hours yielded a sterile dry earthworm powder containing 5~15% water. In particular, the final finishing step, vacuum drying, is a baking soda operation. As a result of detailed research, the present inventor conducted detailed research to make the dried earthworm powder sterile without deactivating the activity of the proteolytic enzymes and enzyme precursors contained in the dried earthworm powder. It was discovered that the combination of the three elements of vacuum drying conditions in the final step of drying, vacuum degree, heating temperature, and time, was an important condition, and the above-mentioned operating conditions were established. As shown above, six types of purified proteolytic enzymes from dried earthworm powder (Japanese Patent Application Publication No. 59-6318
It has been reported that the proteolytic enzyme in the dried earthworm powder obtained by the production method of the present invention is inactivated as shown in Table 4. It has not been. The dried earthworm powder obtained by methods 1 and 2 has a weight of 5 to 45
In the example stored in a closed state at room temperature for 5 years, no mold formation or other physical or chemical deterioration was observed. The earthworms used in the present invention can be any of the earthworms that normally grow, such as red earthworms, striped earthworms, hook earthworms, phthalmia worms, noitsuta worms, Japanese worms, and Japanese worms. Preferred are red earthworms, red earthworms, foot earthworms, and striped earthworms. When the earthworm dry powder of the present invention is administered for clinical treatment, it can be administered in either oral or parenteral form.
Oral administration is particularly preferred. The oral dosage forms of the present invention include capsules, tablets, granules, powders, coatings, sugar-coated tablets, and emulsions. Such formulations are used. Examples of pharmaceutical carriers include excipients such as lactose, sucrose, mannitol, glucose, starch, nrubitol, glycine, calcium phosphate, and microcrystalline cellulose; binders such as starch, gelatin, gum arabic, glucose, sucrose, sorbitol, and mannitol. , tragacanth, hydroxypropylcellulose, dipropoxymethylcellulose in human r3. Carboxymethylcellulose, 2-methyl-5-vinylpyridine-methacrylic acid-methylethyl acrylate copolymer, polyvinylpyrrolidone, sodium alginate, etc.; As a lubricant, stearic acid, hydrogenated oil, magnesium stearate, calcium stearate, polyoxy Ethylene monostearate, Merck, silicon oxide, polyethylene glycol, etc.; Valley ship/as a disintegrant
Starch containing powder, surfactant, etc.; sodium lauryl sulfate etc. as a wetting agent. Furthermore, when administered parenterally, it can be used as a main agent. In particular, cocoa butter, Witepsol (Witep) is used as the main ingredient base.
aol), 5ubanal, polyethylene glycol, polypropylene glycol, brisemic gelatin, gelatin capsules, etc. are used. Others: Methyl parahydroxybenzoate, propylvala hydroxybenzoate, butyl parahydrogen 7
Known safe preservatives such as zoate and butylhydroxyanisole, and other safe dyes are used in combination. The dosage of the earthworm dry powder of the blood pressure regulating agent or antihypertensive agent of the present invention varies depending on the administration method, patient's age, weight, condition, and type of disease, but is usually 0.000 to
．． 01f to 3 is preferable. Most preferably, the dosage is 0.025' to 22' per day, divided into 1 to 3 doses per day. Effect: The pharmacological test method and results of the toxicity and antihypertensive effect or blood pressure lowering of the dried earthworm powder of the present invention will be explained in detail below. A. Acute toxicity test: ticty male mice weighing 30±22 and body weight ]00
An acute toxicity test by oral administration was carried out using ±21 Wiatar male rats (5 animals in each group). Dry earthworm powder M-1 of the present invention (moisture 10.2 k, ash content 5
．． Section 1, containing 9.4% nitrogen); M-2 (moisture 10.4%);
M-3 (moisture 10.7%, ash content 5.2 tlJ, nitrogen content 9.2%)
Same M-4 (moisture 10.6%, ash 5.6%, nitrogen 9.
Same M-5 (moisture 9.5, ash 4.5, nitrogen 7.81); same M-6 (moisture 9.2, ash 4.7, nitrogen 8.4) 0)
．． Increased from 1 t/Kg to 897Kg to 52/'Kf from mouse co,i and rat (from 2 to 8ri/Kf).
In 4), the drugs were administered individually by forced administration using a throat probe. Animals were maintained at an animal room temperature of 22-23° C. during the study period and observed for 14 days after dosing. No deaths were observed at the doses administered. Toxicity and behavior after administration were observed over time, but no differences were observed between the normal animal group and the animals. Furthermore, there was almost no difference in weight gain from the normal animal group. A post-test necropsy did not reveal any macroscopic damage to any part of the main male canal. Therefore, the LD50 value could not be determined for the earthworm dry powder of the present invention due to its very low toxicity. B. Spontaneous hypertensive rats (hereinafter referred to as SHR)
Effect on: Pharmacological test 1 Blood pressure lowering effect on 5HH and heart rate test - 10-12 weeks of age fasted day and night (body federation 00-300?, blood pressure 15
0-200 rrmHg) for male SHR, 0.51
The sample earthworm dry powder (M-4) suspended in an aqueous solution of carboxymethyl cellulose was orally administered at a rate of 4 oap/Kf (the control drug hydralazine hydrochloride was 1 oap/Kf) per 100 capes. .Blood pressure was measured at 6 hours (3-4
(average value for animals). That is, by comparing the blood pressure and heart rate before administration of the sample with the blood pressure and heart rate after administration of the sample,
The blood pressure lowering effect and heart rate increase of the sample were determined. To measure blood pressure, warm the SHR at 45 to 50°C for about 5 minutes, then use an automatic pressure recorder to measure the tail Pl.
ethyamograph method [The fist journal of
The systolic pressure of the caudal artery was measured non-invasively according to Laboratory and Clinical Journal Vol. 78, p. 957 (1971). The test results are shown in Table-51C. The maximum decrease from the systolic pressure before administration was shown as the blood pressure lowering effect. Products obtained by method 1 (M-2 and M-
4) and the dried earthworm powder of all samples of the products (M-5 and M-6) obtained by method 2 were added to SHR in 100 rays.
Oral administration of Ap showed the maximum hypotensive effect 1 to 2 hours after administration. That is, the blood pressure of the SHR is 1ft28-35n
The mHg was lowered and this effect lasted for 6 hours. Furthermore, the results of measuring the increase in heart rate are shown in Table 3. It was found that all of the sample dry earthworm powders did not have any unfavorable side effects on the heart such as M, unlike the control drug hydralazine hydrochloride. Table 5 C0 hemolytic action pharmacological test 2 Earthworm drying of each of the four specimens of products obtained by production method 1 (M-2 and M-4) and products obtained by production method 2 (M-5 and M-・6) Add 5 parts (by weight) of physiological saline to 1 part (by weight) of the powder, suspend the mixture well, and then leave it in a refrigerator at 5°C for 24 hours, filter under reduced pressure, and use liquid F as an aqueous extract. The ethyl alcohol or acetone extract component was 1 part of dry earthworm powder for each of the 4 types of specimens (ii) 5 parts ('31 amount)
After adding ethyl alcohol or acetone and thoroughly suspending, the mixture was allowed to stand at 15-20°C for 24 hours, filtered under reduced pressure, and the solution F was dried under reduced pressure at 40-45°C. This was mixed with physiological saline containing carboxymethyl cellulose for 30 minutes.
Four solutions were prepared. For the hemolytic action, blood is collected from the ear vein of an adult rabbit weighing approximately 3 liters, and the blood is defibrillated. 5.1.0.1.0.01.0.001. Each part of the water extract, ethyl alcohol and acetone extract was mixed with physiological saline.
Dilute to 0.0001 (weight), place these in a small test tube, and drop defibrinated blood into it with a pipette.
After 1 hour, the hemolysis results were determined. The results of this test are shown in Table-
As shown in Figure 6, no hemolysis was observed in any of the dried earthworm powder samples. Table 6 Previous literature reports that as earthworm poison, dried earthworms (Jiryu) have a hemolytic effect that destroys red blood cells [Worms and Life: Written by Mayu Obuchi, October 3, 1947]
0, published by Maki Shobo, pp. 223-226, and reprinted water: written by Shinkiji Hatai, published by Scientist Co., Ltd., April 30, 1980, pp. 160-163]. It has been reported that the aqueous extract and ethyl alcohol extract of Ryu (Japanese dragon) have a partial hemolytic effect [Kenji Iyobu, Niyamaguchi Igaku Vol. 9, pp. 571-576 (1960)]. It has been found that earthworm dry powder has no such hemolytic effect. D. Oral administration test of dried earthworm powder as an antihypertensive agent to humans: 8 hypertensive patients (4 males, 4 females) who consented to this study.
and 6 hypotensive patients (3 males, 3 females) and 4 volunteers (7 males, 7 females).
) K, Capsule A manufactured in Example 4 described below (one capsule contains earthworm dry powder (M-2 above, moisture 10.4
%, ash content 5.3%, nitrogen content 8.696%), capsules E produced in Example 11 [1 capsule contains earthworm dry powder (M-4, water content 10.6%, ash content 5.0%)]. Capsules F manufactured in Example 12 [containing 6 qb, nitrogen 9.6 g) and 150 da] and capsules F produced in Example 12 [1 capsule contains earthworm dry powder (the above M-5, moisture 9.5 k, ash content 4.5 k,
Nitrogen (7.8%) containing 150%' was taken orally, 1 capsule at a time, 3 times a day, within 30 minutes after breakfast, lunch, and dinner. The administration was carried out weekly for 2 to 11 months while observing the symptoms once every 1 month.The results are shown in Table 7. approximately the same number of 30 mm
I lowered my Hg around. In other words, the systolic blood pressure of a hypertensive patient is 3
0-39 mmHg, diastolic blood pressure 26-34 mmHH
lowered blood pressure. After blood pressure reached normal values, normal maintenance was observed for 3 to 7 months. Furthermore, when administered to hypotensive patients, it increased blood pressure by 15-30 rrmHg. That is, if the systolic blood pressure of a hypotensive patient is reduced to 20-30 r
The rmHg was raised, and the diastolic blood pressure was increased by 15 to 22 ntrt (g). After reaching normal values, normal blood pressure was maintained for 3 to 5 months. During long-term administration for 2 to 11 months, there was no abnormal decrease and/or increase in human blood pressure, and no other side effects were observed.Comprising the dried earthworm powder of the present invention as an active ingredient Blood pressure regulators or anti-hypertension agents have a mild blood pressure lowering and/or blood pressure increasing effect in humans, cause mild lowering and/or blood pressure increase, and can be used as preventive agents in addition to therapeutic agents for hypertension and hypotension. It was also found that the drug is safe and can be administered for a long period of time.Example 1 below: Tablet A Dry earthworm powder 150119 (components are the same as M-3 above) Manitol 123 hydroxyproboxymethylcellulose 7 Tal
the law of nature
5 Microcrystalline cellulose 6°,
Hydrogenated castor oil 5 total 350j
9 Tablet B Dry earthworm powder 15019 (Ingredients are the same as M-3 above) Cornstarch powder 60 Milk
Sugar 80t
Ruri
7 Magnesium stearate 3
Total of 300 tablets C Dry earthworm powder 150 kg (Ingredients are the same as M-3 above) Soluble starch 20 Corn starch 125 Microcrystalline cellulose
45 silicon oxide 6
Magnesium Stearate Total of 4 3509 Tablets of various weights were manufactured using a tablet machine using a uniform and well-mixed powder according to the above recipe. Example 2. Granules A Dry earthworm powder 150 kg (Ingredients are the same as M-2 above) Lactose 2
0 Microcrystalline cellulose 60 Corn starch 15 Hydroxypropyl cellulose 5 Total 250 kg According to the above recipe, using a fluidized bed granulator, dry earthworm powder, milk spears, microcrystalline cellulose and corn starch were thoroughly mixed, and hydroxypropyl A 51 aqueous solution of cellulose was sprayed as a binder and granulated after drying at low temperature. Example 3゜ Granule B Contains dry earthworm powder 100 kg (components are the same as above M-2) Manitol 10 Microcrystalline cellulose 85 Carboxymethyl cellulose calcium 2 Magnesium stearate
1.5 Hydrogenated oil 1.5 Total 200.0kg Granules C Dry earthworm powder 150q (Ingredients are the same as M-2 above) Lactose
53 Corn starch flour 39 Potato starch flour 2 tal.
3 Magnesium stearate 3 total 2507 grains According to the above recipe, the well-mixed powder was used in an extractor to produce granules. Example 4. Capsule A Dry earthworm powder 1501'ILI (components are the same as M-2) Lactose 2
8 Microcrystalline cellulose 47 Mannitol lO corn starch flour
10 polyvinylpyrrolidone
2 Hydroxypropyl cellulose 3 total 250 ~ Among the above formulations, the components other than hydroxypropyl cellulose were well mixed using a fluidized bed granulator, then a 59b aqueous solution of hydroxypropyl cellulose was sprayed as a binder, and after drying at low temperature. It was made into granules. Hard capsules were prepared by filling 250 to 250 granules into hard capsules. Example 5. Capsule B Granules C produced according to Example 3 were put into hard capsules, and 25
Hard capsules were prepared by filling 0.5 ml each. Example 6. Capsule C Dry earthworm powder 150119 (Ingredients are the same as M-3 above) Calcium hydrogen phosphate 60 Sodium hydrogen phosphate 10 Manitol
28 Magnesium stearate 2 total 25
0q The above formulation was thoroughly mixed and 250++ vf of gelatin capsules of this mixed powder eA1 were filled to produce capsules. Example 7. Enteric-coated tablet earthworm dry powder 100iy (components are the same as above M-Ll) Manitol 10 Microcrystalline cellulose 85 Carboxymethyl cellulose calcium 2 Magnesium stearate
1.5 Hardening agent 1.5 Total 200η According to the above recipe, the uniformly mixed powder is manufactured into uncoated tablets using a tablet press, and then coated with the following i-solvent coat coating agent to form enteric-coated tablets. Manufactured. Coating agent hydroxypropyl methyl cellulose phthalate 14.
8~ Dioctyl phthalate 2.3 Stearic acid 2.3 Light silicon oxide
0.6 total 20.0 ~ Example 8. Powder A Dry earthworm powder 150 ~ (Ingredients are the same as M-4 above) Manitol 50 Cornstarch 50 Total 250η Powder B Dry earthworm powder 15011g (Ingredients are the same as M-4 above) Calcium phosphate-hydrogen 2゜Corn starch flour 8゜Total 250M? The above components were mixed thoroughly and uniformly in a conical mixer to form a powder. Example 9. Suppositories A Dry earthworm powder 200q (Ingredients are the same as M-5 above) Witepsol 540 (Witeps
ol) E-85 Witepsol 1,454 (#) W-3
5 Methylbara hydroxybenzoate 3
Butyl parahydroxybenzoate 3
Total 2.200η Suppository B Earthworm dry powder 200q (Ingredients are the same as above M-6) Butylhydroxyanisole 6 Semi-synthetic glyceride 2,900 Total 3.106 ~ Mix the above formulations well; was poured into an aluminum mold and cooled to produce a base ingredient. Example 10. Capsule D Earthworm dry powder 150'V (Ingredients are the same as M-2 above) Sodium laurate 4 Sodium hydrogen phosphate 1 Manitol
93 Magnesium stearate 2 total 250 capes Mix the above formulations well. Add this mixed powder to 41
Capsules were prepared by filling 250 q of the mixture into gelatin capsules. Example 11. Capsule E Dry earthworm powder 150 capes (components are the same as M-4 above) Calcium hydrogen phosphate 60 Sodium hydrogen phosphate 10 Manitol
28 Magnesium stearate 2 total 25
0q The above-mentioned discarded material was thoroughly mixed, and 250,119 gelatin capsules each of this mixed powder tA1 were filled to produce capsules. Example 12. Capsule F Earthworm dry powder 150++v (Ingredients are the same as M-5 above) Sodium laurate Sodium diphosphate-hydrogen 4 Anitole
92 Magnesium stearate 2 total 2
50■ Mix the above formulation thoroughly. This mixed powder is A1
Each gelatin capsule was filled with 250 η to produce a capsule. Effects of the Invention: As stated above, the present invention relates to a blood pressure regulator or antihypertensive agent comprising dried earthworm powder as an active ingredient. The dried earthworm powder obtained in the present invention has no side effects such as hemolytic effect and tachycardia, is safe, has excellent blood pressure lowering effect and blood pressure increasing effect, has good storability or storability, and is sterile. could be obtained in high yield. Next, a total of 14 volunteers (8 hypertensive patients and 6 hypotensive patients) were given 1 dose of earthworm dry powder capsules (concentration: 150 capes) orally three times a day after breakfast, lunch, and dinner. 2η
The drug was administered for 11 months. The preparation of the present invention has the effect of lowering the blood pressure of hypertensive patients, increasing the blood pressure of hypotensive patients, and bringing human blood pressure to normal levels. Moreover, the blood pressure that reached the normal value with the preparation of the present invention was maintained at a normal blood pressure for 3η7 months. During this period of administration, no abnormal decrease and/or increase in human blood pressure occurred, and no other side effects were observed. That is, the laceration of the present invention was found to be a safe and excellent blood pressure regulating agent, antihypertensive agent, or preventive agent for hypertensive and hypotensive disorders.

Claims (1)

[Claims] 1. A blood pressure regulator comprising dried earthworm powder as an active ingredient. 2. Live earthworms were treated with 0.3% (by weight) of at least one compound selected from the group consisting of organic acids, inorganic acids, organic acid sodium salts, inorganic acid sodium salts, organic acid potassium salts, and inorganic acid potassium salts. After leaving the living earthworms in an aqueous solution containing the following or in fresh water to remove the excrement in their digestive tracts, the filth adhering to the body surface of the live earthworms is washed away with water, and then wet pulverization is performed to create a suspension. -10~-
After freezing at 60°C, the temperature was raised stepwise within the range of -60 to 80°C and the vacuum level was 10 mmHg or less.
Freeze and vacuum dry for ~100 hours, including the final step of vacuum drying at 70 to 80°C to a thickness of 0.01 to 0.5 mm.
A blood pressure regulator comprising dried earthworm powder as an active ingredient, which is dried under Hg vacuum for 5 to 10 hours. 3. After washing and removing dirt adhering to the body surface of the live earthworms with water, the live earthworms are treated with a group consisting of organic acids, inorganic acids, organic acid sodium salts, inorganic acid sodium salts, organic acid potassium salts, and inorganic acid potassium salts. After leaving in an aqueous solution containing 0.3% (weight) or less of at least one compound selected from the following or in fresh water to remove the excrement from the digestive tract of a living earthworm, wet crushing is performed to remove this suspension. -1 for cloudy liquid
After freezing at 0 to -60°C, freezing and vacuum drying are performed for 10 to 100 hours at a vacuum level of 10 mmHg or less while raising the temperature stepwise within the range of -60 to 80°C. Dry at 70-80°C at 0.01-0.
A blood pressure regulator comprising dried earthworm powder as an active ingredient, which is dried under a vacuum of 5 mmHg for 5 to 10 hours.