JPH06227997A - Diuretic - Google Patents

Abstract

PURPOSE:To provide a diuretic exhibiting its effect in an infinitesimal amount. CONSTITUTION:A substance contained in SAIREITO (kind of Chinese drug) and reactive with anti-digoxin antibody and a diuretic containing this substance as the active component.

Description

Detailed Description of the Invention [Industrial applications]

The present invention relates to diuretics.

[Prior Art and Problems]

Conventionally, spinolactone, furosemide, acetazolamide and the like have been used as diuretics, but these drugs had side effects such as electrolyte imbalance, metabolic disorders, loss of appetite and nausea. Therefore, it has been further desired to develop a new diuretic with less side effects.

[Means for Solving the Problems]

The inventors of the present invention have been able to obtain various Kampo prescriptions.
As a result of research on diuretic action, the substance extracted from Sairei-to has an excellent diuretic action.
They found that even a very small amount has a diuretic effect, and completed the present invention.

That is, the present invention relates to (1) a substance which reacts with anti-digoxin antibody by mixing water or an organic solvent containing water with stirring, separating the supernatant after stirring, and removing the organic solvent. This substance is referred to as the substance of the present invention.) And (2) above
A diuretic containing the substance obtained in (1) as an active ingredient.

Sairei-to, which contains the substance of the present invention, is a Chinese herbal medicine used for hydrodiarrhea, acute gastroenteritis, hot air, swelling, and the like. Hmm,
It is made of herbal medicines such as soy sauce, oju, boar, carrot, sardine, licorice, cinnamon, and ginger.

[0006] The composition ratio of this Sairei-to is determined according to the classical Chinese herbs, but the classical Chinese herbs have a wide range of ratios of the herbal medicines, and the natural herbs are dependent on the natural conditions such as the place of origin, sampling time, and weather. The amount of ingredients contained varies. Therefore, the mixing ratio of each constituent crude drug needs to be appropriately increased or decreased, but it is generally produced by the following mixing ratio. Saiko 4 ~ 7 Sawarei 5 ~ 6 Half summer 4 ~ 5 Yellow goat 3 Sogaku 3 ~ 4.5 Ohju 2 ~ 3 Botan 3 ~ 4.5 Ginseng 2 ~ 3 Ginseng 3 ~ 4.5 Licorice 2 Kelp 2 ~ 3 Ginger 1 ~ 4

To obtain the substance of the present invention, for example, the following methods can be mentioned.

[0008] Water or an organic solvent containing water is mixed with Saireito and stirred (preferably 10 minutes or more under a temperature condition of 4 ° C or more)
Then, centrifuge (10 minutes or more under conditions of 100 xg or more) to separate the supernatant. The organic solvent in the supernatant is removed, and the supernatant is dissolved in a coupling buffer [0.1 M NaHCO ₃ , pH 8.3 containing 0.5 M NaCl]. A gel to which an anti-digoxin antibody is bound is added to this solution and stirred (at a temperature at which the antibody does not denature, preferably at 0 ° C to 40 ° C for several minutes to several hours). The substance of the present invention can be obtained by washing the gel (several times), adding water or an organic solvent containing water to the gel to separate the substance of the present invention, and further removing the solvent.

Specific examples of the organic solvent used for obtaining the substance of the present invention include ethanol, methanol, butanol, acetone, chloroform, ethyl acetate and hexane.

Next, the present invention will be described in more detail by showing examples of the substance of the present invention and experimental examples using the substance of the present invention.

[Example] 1 g of Saireito extract powder and 10 ml of 80% ethanol were mixed and stirred at room temperature for 2 hours, and then 2500 rpm.
The supernatant was separated by centrifugation at (800 xg) for 10 minutes. Ethanol was removed using a rotary evaporator, and the residue was redissolved in 4 ml of coupling buffer [0.1 M NaHCO ₃ , pH 8.3 containing 0.5 M NaCl]. Add anti-digoxin IgG antibody (anti-Digoxi
CNBr-activated Sepharose 4B conjugated with (n IgG antibody)
Gel (anti-Digoxin IgG antibody immunosorbent gel: Pharmaci
a LKB Biotechnology) 2 ml was added, and the mixture was stirred at room temperature for 2 hours. Coupling buffer [0.5M NaCl addition 0.1MN
aHCO ₃ , pH 8.3] was washed 5 times by centrifugation and the supernatant was removed.
Add 10 ml of 0% ethanol and stir for 1 to 2 minutes.
After centrifugation at 30 × g) for 15 minutes, the supernatant was collected. 41.6 ng of the compound of the present invention was obtained by removing ethanol from the collected supernatant using a rotary evaporator.

[Experimental Example] A rat weighing about 500 g was anesthetized with 25% urethane (2.5 to 3.0 ml), and then a cartel was inserted into the femoral artery to measure blood pressure, and at the same time, physiological saline (containing 0.05% creatinine) was used. ) The solution was infused at 3 ml / hour. A cartel was placed in the bladder, and urine was collected every 30 minutes.When the blood pressure and urine volume became stable, 7.5 ng of the test drug dissolved in 2 ml of physiological saline was injected through the tail vein over a period of several minutes. Urine was collected every minute, and urine volume and urinary Na / creatinine level were measured as indicators of diuretic effect.

The results are shown in Table 1. From this experiment, as shown in Table 1, it was confirmed that the compound of the present invention has a diuretic effect.

Table 1

Next, the dose and formulation of the substance of the present invention will be described.

The substance of the present invention can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier.
The dosage form is not particularly limited and may be appropriately selected and used as necessary, and may be tablets, capsules, granules, fine granules,
Examples thereof include oral agents such as powders, parenteral agents such as injections and suppositories.

In order to exert a desired effect as an oral preparation, it varies depending on the age, body weight and degree of disease of the patient, but usually the dose of the substance of the present invention is 1 μg per adult in a single dose.
It is suitable to take ~ 10 μg and take 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 disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring agent and the like may be appropriately used in this type of preparation. You can
Specific examples of each are as follows.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose,
Ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 8
0.

[Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Flowability Accelerator] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The substances of the present invention can also be administered as suspensions, emulsions, syrups and elixirs, and these various dosage forms may contain flavoring agents and coloring agents. Good.

In order to exert a desired effect as a parenteral agent, it depends on the age, body weight and degree of disease of the patient.
Usually 0.1 μg to 1 μg / day as the weight of the substance of the present invention in adults
Intravenous injection, intravenous drip infusion, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured by a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericide, 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 and then frozen, the water content may be removed by a usual freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as needed.

Other parenteral agents include external preparations, coating agents such as ointments, and suppositories for rectal administration.
It is manufactured according to a conventional method.

Next, the formulation examples of the present invention will be described.

[Formulation Example 1] Corn starch 47.9985 g Crystalline cellulose 45 g Carboxymethyl cellulose calcium 6 g Light anhydrous silicic acid 0.5 g Magnesium stearate 0.5 g Compound obtained in Examples 1.5 mg Total 100 g

According to the above formulation, the ingredients (1) to (2) were uniformly mixed and compression-molded with a tableting machine to give tablets (200 mg each).

One tablet of this tablet contains 3 μg of the compound obtained in the Example, and 1 to 3 tablets for adults are to be taken in several divided doses per day.

[Formulation Example 2] Crystalline cellulose 85.4985 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Compound obtained in Example 1.5 mg Total 100 g

According to the above formulation, a part of and was uniformly mixed, compression-molded, crushed, and the remaining amount of and was added and mixed.
0 mg tablets were obtained.

One tablet of this tablet contains 3 μg of the compound obtained in the Example, and 1 to 3 tablets for adults are to be taken in several divided doses per day.

[Formulation Example 3] Crystalline cellulose 80.4985 g 10% Hydroxypropyl cellulose ethanol solution 50 g Carboxymethyl cellulose calcium 5 g Magnesium stearate 0.5 g Compound obtained in Example 1.5 mg Total 100 g

According to the above formulation, and were uniformly mixed, and the mixture was kneaded by a conventional method, granulated by an extrusion granulator, dried and crushed, and then mixed, and compressed by a tableting machine. It was molded to obtain a tablet of 200 mg each.

One tablet of this tablet contains 3 μg of the compound obtained in the example, and 1 to 3 tablets for adults are to be taken in several divided doses per day.

[Formulation Example 4] Corn starch 84.9985 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Compound obtained in Example 1.5 g Total 100 g

According to the above formulation, the components (1) to (4) are uniformly mixed, compression-molded by a compression molding machine, and crushed by a crusher
Sieve to obtain granules.

1 g of this granule contains 15 μg of the compound obtained in the example, and 0.2 to 0.6 g of an adult is taken in several divided doses per day.

[Formulation Example 5] Crystalline cellulose 87.4985 g 10% Hydroxypropyl cellulose ethanol solution 35 g Compound obtained in Example 1.5 mg Total 100 g

According to the above-mentioned recipe, the ingredients (1) to (4) were uniformly mixed and kneaded. After granulating with an extrusion granulator, it was dried and sieved to obtain granules.

1 g of this granule contains 15 μg of the compound obtained in Example, and 0.2 to 0.6 g of an adult is taken in several divided doses per day.

[Formulation Example 6] Corn starch 90.4985 g Light anhydrous silicic acid 0.5 g Compound obtained in Example 1.5 mg Total 100 g

According to the above-mentioned formulation, 1 to 3 were mixed uniformly, and 200 mg was filled in a No. 2 capsule.

One capsule of this capsule contains 3 µg of the compound obtained in the example, and 1 to 3 capsules for adults are to be taken in several divided doses per day.

Formulation Example 7 Distilled water for injection Appropriate amount Glucose 200 mg Compound obtained in Example 0.5 μg Total amount 5 ml

After dissolving and in distilled water for injection, the mixture was poured into a 5 ml ampoule and autoclaved at 121 ° C. for 15 minutes to obtain an injection.

[Formulation Example 8] Crystalline cellulose 50.0 parts (trade name: Asevir PH-301, manufactured by Asahi Kasei Corporation) Lactose 18.0 parts Carboxymethyl cellulose sodium 2.0 parts (CMC-Na, trade name Serogen F, Daiichi Kogyo Seiyaku Co., Ltd.) (Manufactured) lactose of the compound obtained in the example 10000 times dispersion 30.0 parts total 100.0 parts

The above-mentioned proportions of the formulations were mixed and compression-molded to give a sublingual tablet of 100 mg per tablet.

One tablet of this tablet contains 3 μg of the compound obtained in the Example, and 1 to 3 tablets for adults are to be taken in several divided doses per day.

[Formulation Example 9] Gum arabic powder 60.0 parts White sugar 50.0 parts Lactose 37.0 parts Lactose of the compound obtained in the example 10000 times dispersion 10.0 parts Perfume Trace amount

3 parts of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added to 157 parts of a powder obtained by mixing the above-mentioned proportions, kneading with water, kneading, sizing and drying, and compression-molding. , 1 tablet gave a sublingual tablet of 160 mg.

One tablet of this tablet contains 1 μg of the compound obtained in the Example, and 1 to 10 tablets for adults are to be taken in several divided doses per day. that's all

Claims (2)

[Claims] 1. A substance which reacts with an anti-digoxin antibody by mixing water or an organic solvent containing water into Sairei-to, stirring and separating the supernatant. 2. A diuretic containing the substance obtained in claim 1 as an active ingredient.