JPH0782165A - Antimalarial agent - Google Patents

Abstract

PURPOSE:To obtain an antimalarial agent having high safety by using a crude drag mixture or its extract as an active component. CONSTITUTION:This antimalarial agent contains OUGI (root of Astragalus huantchy), KEIHI (bark of Cinnamomum cassia), JIOU (root of Rehmannia glutinosa), SHAKUYAKU (root of Paeonia albiflora), SENKYU (rhizome of Cnidium officinale), SOUJUTSU (rhizome of Atractylodes lancea), TOUKI (root of Angelica acutiloba), NINJIN (rhizome of Panax ginseng), BUKURYO (sclerotium of Poria cocos) and KANZOU (root of Glycyrrhiza glabra) or their extracts as active components.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an antimalarial agent containing a mixed crude drug or an extract thereof as an active ingredient.

[0002]

Malaria is an infectious disease caused by the parasite of Malaria plasmodium mediated by Anopheles medaka. At present, no malaria vaccine has been established, and therefore, anti-malarial drugs such as quinine, chloroquine, primaquine, and quinacrine are known as anti-malarial drugs.

However, as typified by chloroquine retinopathy, conventional antimalarials have problems in safety and drug resistance. Therefore, development of a new type of antimalarial drug with high safety is desired. On the other hand, yellow radish, cinnamon, ground yellow, peony, river cucumber, blue
Juzen-daiho-to, which is composed of ginseng, carrot, licorice, and licorice, has pharmacological effects such as immunostimulatory action, leukocyte reduction / weight loss prevention effect, toxohormone L activity inhibitory effect, and vasodilatory effect. It has been used to reduce physical fitness after illness, fatigue, loss of appetite, rash, cold hands and feet, anemia, etc., but it has not been used as an antimalarial drug.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a highly safe antimalarial agent containing a mixed crude drug or an extract thereof as an active ingredient.

[0005]

DISCLOSURE OF THE INVENTION The present invention is directed to Astragalus sinensis, cinnamon,
It is an antimalarial agent containing ground yellow peony, peony, river cucumber, soy sauce, toki, carrot, peony and licorice, or extracts thereof as an active ingredient. The blending ratio of each crude drug in the antimalarial agent of the present invention is preferably 2-3 parts by weight of Radix Astragali, 2 to cinnamon bark.
3 parts by weight, ground yellow 3-4 parts by weight, peony 3-4 parts by weight, river cucumber 3-4 parts by weight, soy sauce 3-4 parts by weight, toki 3-4 parts by weight, carrot 2-3 parts by weight, 苓苓 3 ~ 4 parts by weight and licorice 1 ~
2 parts by weight.

An example of a Kampo prescription consisting of each crude drug in such a preferable mixing ratio is, for example, Juzentaihoto. The above-mentioned prescription of Juzen-taiho-to is described in the classical Chinese herbal formula (Kintai et al.) And there are some differences, but the range of each crude drug is generally as follows. [Juzen Taihoto] 3 parts by weight of yellow radish 3 parts by weight of cinnamon 3 parts by weight of yellow ground 3 parts by weight of peony root 3 parts by weight of river cucumber 3 parts by weight of soy sauce 3 parts by weight of ginseng 3 parts by weight 3 parts by weight of liquorice licorice 1.5 Parts by Weight As the extract of the crude drug, various aqueous solvent extracts can be mentioned, but it is preferable to use the water extract. As a concrete example of preparation of the extract, the crude drug mixture having the above composition was used.
An example is a method of extracting with ~ 20 times the amount of hot water and filtering the resulting extract. This extract can be dried if necessary and used as a dry powder.

A specific example of the production of the active ingredient of the present invention is as follows. Specific Example 1 3 g of yellow radish, 3 g of cinnamon bark, 3 g of ground yellow, 3 g of peony, river cucumber 3
28 g for a mixed crude drug of g, 3 g of soy sauce, 3 g of toki, 3 g of ginseng, 3 g of 苓苓, and 1.5 g of licorice (Juzentaihoto: 28.5 g)
5 ml of distilled water was added and the mixture was decocted to half the volume, and the obtained extract was filtered and freeze-dried to obtain 5.0 g of dried extract.

Specific Example 2 300 g of yellow radish, 300 g of cinnamon bark, 300 g of ground yellow, peony root 30
0g, river cucumber 300g, souhou 300g, toki 300
28.5 L of purified water was added to a mixed crude drug (juzentaihoto: 2.85 kg) of g, carrot 300 g, boiled peony 300 g, and licorice 150 g, and the mixture was heated and extracted at 100 ° C. for 1 hour. The obtained extract was centrifuged and the residue was separated to obtain a solution.

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

Next, the fact that the active ingredient of the present invention is effective against malaria infection will be described with reference to experimental examples. Experimental Example In a mouse in which human granulocyte colony stimulating factor (G-CSF) was administered to induce division / differentiation of bone marrow stem cells into neutrophils, it was examined whether the active ingredient of the present invention may affect malaria infection. did.

[0011] Plasmodium berghei X is a weakly virulent protozoa which takes a chronic course of infection and spontaneously cures against malaria parasite infection.
AT strain was used. Infection was 5 weeks for each 7-week-old CBA female mouse
The test was performed by inoculating 1 × 10 ⁴ infected red blood cells intravenously to a mouse.
Two days before infection, 2 g / kg (orally administered) of the active ingredient of the present invention (dried extract obtained in Example 1) and / or G-CS
F250 μg / kg (subcutaneous administration) was continuously administered for 18 days, and the effect on malaria infection was observed by comparing the protozoalemia rates in the control group (both oral administration of distilled water and subcutaneous administration of physiological saline) and the administration group. . The results are shown in Fig. 1.

As shown in FIG. 1, 5% of the control mice were
After maintaining the above-mentioned protozoalemia rate, it spontaneously healed after about 4 weeks. However, in the groups to which the active ingredient of the present invention and G-CSF were administered alone or in combination, the protozoalemia rate was 2 weeks after the infection. Remarkably decreased. Regarding protozoan-specific IgG antibody production in mice after malaria infection, the antibody titer of the administration group is high, and IgG is said to be particularly involved in the defense of infection.
Production of the 2a subclass was significantly increased compared to the control group. This tendency was particularly remarkable in the combined administration group of the active ingredient of the present invention and G-CSF. The details of the results are shown in Table 1.

[0013]

[Table 1]

In Table 1, I is the active ingredient of the present invention and G
-CSF is a combined administration group, II is G-CSF, III is a single administration group of the active ingredient of the present invention, and IV is a control group. From the above results, it was confirmed that the active ingredient of the present invention is effective against malaria infection. Next, an acute toxicity test of oral administration of Juzentaihoto, which is the active ingredient of the present invention, was carried out by ddY.
When the test was performed using male mice of the Strain type and male rats of the Wister type, the dried extract obtained in Example 1 was 15 g / kg.
Even in oral administration of (marginal administration), no occurrence of death was observed. Thus, the antimalarial agent of the present invention,
It has extremely low toxicity.

Next, the formulation and dose of the antimalarial agent of the present invention will be described. The antimalarial agent of the present invention can be formulated by using each crude drug of the above formulation as it is or by combining the extract thereof with a known pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, parenteral preparations such as injections and suppositories. To be

In order to exert the intended effect, it depends on the age, body weight and degree of disease of the patient, but it is usually 0.9 to 15 as the weight of the active ingredient of the antimalarial agent of the present invention in an adult.
It is suitable to take g in several divided doses per day. The oral preparation is produced by a conventional method using starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like.

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, etc. may be appropriately used in this type of formulation. You can
Specific examples of each are as shown below. [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 80.

[Lubricant] Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol. [Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The antimalarial agent of the present invention is a suspension,
It can also be administered as an emulsion, syrup, or elixir, and these various dosage forms may contain a flavoring agent and a coloring agent. On the other hand, parenteral preparations are manufactured according to a conventional method, and are generally used as diluents 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 and the like can be used. Further, if necessary, a bactericidal agent, a preservative, and a stabilizer may be added. In addition, this parenteral agent is stable,
It is also possible to fill the vial and the like and then freeze, remove water by a usual freeze-drying technique, and re-prepare the liquid agent from the freeze-dried product immediately before use. Further, if necessary, a tonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added appropriately.

[0021]

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

This granule is a single dose of 0.
5-4.5 g (0.1% as a dry extract which is an active ingredient)
34 to 3.10 g) 3 times a day. Example 2 200 g of the dried extract obtained in Example 1 was mixed with 20 g of microcrystalline cellulose and 5 g of magnesium stearate, and this mixture was tabletted with a single-shot tableting machine to produce a tablet having a diameter of 7 mm and a weight of 225 mg. did. One tablet of this tablet contains 200 mg of a dry extract as an active ingredient. This tablet is taken at a dose of 2 to 16 tablets three times a day according to the symptoms.

[0023]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a highly safe antimalarial agent containing a mixed crude drug or an extract thereof as an active ingredient.

[Brief description of drawings]

FIG. 1 is a graph showing the effects of the active ingredient of the present invention and granulocyte colony stimulating factor (G-CSF) on malaria infection.

[Explanation of symbols]

 ▲ Combination administration group of the active ingredient of the present invention and G-CSF □ G-CSF single administration group ● Active ingredient single administration group of the present invention △ Control group

Claims (2)

[Claims] 1. An anti-malarial agent containing, as an active ingredient, yellow radish, cinnamon bark, ground yellow peony, peony root, river cucumber, soy sauce, toki, carrot, peony and licorice, or extracts thereof. 2. The antimalarial agent according to claim 1, wherein the active ingredient is Juzentaihoto or its extract.