JPH0640931A - Enhancer for therapeutic effect on autoimmune disease - Google Patents

Abstract

PURPOSE:To obtain an enhancer for therapeutic effects of an adrenocortical hormone on autoimmune diseases. CONSTITUTION:The objective enhancer for therapeutic effects of an adrenocortical hormone on autoimmune diseases comprises an extract of NINJIN-YOEITO composed of Ginseng Radix (2.0-4.0 pts.wt.), Ligustici Radix (3.0-5.0 pts.wt.), Paeoniae Radix (1.0-5.0 pts.wt.), Rehmanniae Rhizoma (3.0-5.0 pts.wt.), Atractylodis Rhizoma (3.0-5.0 pts.wt.), Hoelen (3.0-5.0 pts.wt.), Cinnammomi Cortex (1.5-3.5 pts.wt.), Astragali Radix (0.5-3.5 pts.wt.), Aurantii Nobilis Pericarpium (1.0-3.5 pts.wt.), Polygalae Radix (0.5-3.0 pts.wt.), Schizandrae Fructus (0.5-2.5 pts.wt.) and Glycyrrhizae Radix (0.5-2.5 pts.wt.) as active ingredients.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug for enhancing the therapeutic effect of corticosteroids on autoimmune diseases. More specifically, it relates to an agent for enhancing the therapeutic effect of corticosteroids on autoimmune diseases, which contains an extract of Ninjin-yoeito as an active ingredient.

[0002]

2. Description of the Related Art An autoimmune disease is a disease in which tissue damage or dysfunction occurs as a result of the action of an antibody or immunocompetent cell having specificity for a body component (self antigen) of self. Diseases classified as autoimmune diseases include systemic lupus erythematosus and rheumatoid arthritis, as well as Hashimoto's disease, glomerulonephritis, allergic encephalitis, ulcerative colitis, autoimmune hemolytic anemia, Sjogren's syndrome. There are various types of organ-specific ones.

Although the adrenal cortex hormone has been found to be useful as a symptomatic therapeutic agent for various autoimmune diseases, a large amount of long-term continuous administration causes induced infection, secondary adrenocortical dysfunction, peptic ulcer, diabetes, etc. There is a limit to the dosage that can be used for treatment because serious side effects of

On the other hand, it has been conventionally known that Ninjinyoeito is effective against physical deterioration after illness, fatigue, anorexia, night sweats, and anemia. It is also known to enhance the carcinostatic action of tegafur (JP-A-61-1940).
(See No. 31).

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide an adjuvant for treating autoimmune diseases, which enhances the therapeutic effect without increasing the dose of corticosteroid.

[0006]

The present inventors have found that Ninjinyoeito extract enhances the therapeutic effect of corticosteroids on autoimmune diseases, and completed the present invention based on this finding.

The composition (mass ratio) of ginseng yoeito in the present invention is ginseng (2.0 to 4.0) and toki (3.0 to 5.
0), peony (1.0 to 5.0), ground yellow (3.0 to 5.
0), Hakushu (3.0 to 5.0), Furei (3.0 to 5.).
0), cinnamon (1.5 to 3.5), and Astragalus (0.5 to 3.).
5), Chen skin (1.0-3.5), distant (0.5-3.
0), Gomiko (0.5-2.5) and Licorice (0.5-)
2.5), preferably ginseng (3.0), toki (4.0), peony (2.0 to 4.0), ground yellow (4.
0), Hakushu (4.0), Furei (4.0), cinnamon (2.0)
~ 2.5), Astragalus (1.5-2.5), Chen skin (2.0-
2.5), Enshi (1.5-2.0), Gomiko (1.0-
1.5) and licorice (1.0-1.5).

The ginseng yoeito extract can be produced as follows. First, 5 to 25 times by weight, preferably 8 to 20 times by weight of extraction solvent is added to Ninjinyoeito,
This is usually heated at 80 to 100 ° C. for 30 minutes to 2 hours to obtain an extract. Water, a water-soluble organic solvent, or a mixed solvent thereof is used as the extraction solvent. Ethanol is preferred as the water-soluble organic solvent.

Next, the extract is filtered or centrifuged to remove insoluble matter, and then concentrated by a conventional means such as concentrated under reduced pressure to obtain a concentrated extract, or further dried by a conventional means such as reduced pressure drying or spraying. Dry or freeze-dry to give a dry extract powder.

The agent for enhancing the therapeutic effect on autoimmune diseases of the present invention (hereinafter referred to as the agent of the present invention) is the above-mentioned concentrated extract, dried extract powder and capsules, granules, tablets, fine granules, powders or liquids containing them. Including various formulations such as. These various preparations, if necessary, excipients, usual pharmaceutical additives such as disintegrants, such as lactose, starch, crystalline cellulose, carboxymethylcellulose calcium,
It can be produced by a conventional method by adding anhydrous silicic acid, synthetic aluminum silicate, magnesium stearate and the like.

The drug of the present invention is orally administered to a patient with autoimmune disease for the purpose of enhancing the therapeutic effect of adrenocortical hormone, simultaneously with or before or after the administration. The dose of the drug of the present invention is not constant depending on the condition, age, weight, etc. of the patient, but usually 0.3 to 10 g of dry extract powder per day for an adult or 2 to
Oral administration is given in 3 divided doses. In the case of a corticosteroid, such as prednisolone, used in combination with the drug of the present invention, 1
The daily dose of 5 to 60 mg is administered once or in 2 to 4 divided doses.

[0012]

The drug of the present invention exhibits a synergistic effect when used in combination with an adrenocortical hormone in the treatment of autoimmune diseases and exhibits an excellent therapeutic effect.

The effect of the drug of the present invention is confirmed by, for example, the preventive effect on the onset of autoimmune disease model mice (MRL / lpr mice). That is, when the drug of the present invention is used in combination with a no-effect dose of prednisolone, which is a corticosteroid, MRL / lpr
Four autoimmune conditions characteristic of mice (lymphadenopathy,
Urinary protein levels, hair loss, and dermatitis) were suppressed, and synergistic effects were observed as compared with the cases where they were used alone (see Test Example 1 below). On the other hand, the toxicity of the drug of the present invention is low (Test Example 2).
reference). Therefore, the drug of the present invention can be effectively and safely used as a drug for enhancing the therapeutic effect of corticosteroids on autoimmune diseases.

The effects of the present invention will be described below in more detail with reference to test examples. [Test Example 1] Suppressing effect on autoimmune symptom development (1) Samples The ginseng yoeito dry extract powder (Example 1) and the prednisolone powder (manufactured by Hanai Yakuhin) of the agents of the present invention were used. (2) Test method (2-1) Administration method 6-week-old female MRL / lpr mice (purchased from CLEA Japan, Inc.)
The test was divided into 4 groups: (a) control group, (b) prednisolone administration group, (c) Ninjinyoeito dry extract powder administration group, and (d) prednisolone and Ninjinyoeito dry extract powder combination administration group. . The sample was dissolved or suspended in 50% propylene glycol / phosphate buffer, and the sample concentration was set according to the body weight of the mouse so that the administration liquid amount was 0.2 ml. Only 50% propylene glycol / phosphate buffer in group (a),
Prednisolone was orally administered to group (b), ginseng yoeito dry extract powder to group (c), and prednisolone and ginseng yoeito dry extract powder to group (d) at the same time (see Table 1). . The administration of the sample was started at 6 weeks of age, and was administered 6 times a week.

[0015]

[Table 1]

(2-2) Method for measuring incidence of autoimmune symptom-bearing mice The four autoimmune symptoms characteristic of MRL / lpr mice are the axillary lymphadenopathy, proteinuria, dermatitis otitis, and alopecia. The onset of autoimmune symptoms was selected, and the onset of autoimmune symptoms was observed in accordance with the following criteria (1) to (3). Then, the ratio (%) of the number of mice determined to develop autoimmune symptoms was defined as the appearance rate of mice with autoimmune symptoms. Axillary lymphadenopathy A lymph node with a diameter of 7 mm or more was regarded as a positive autoimmune condition. Proteinuria A semi-quantitative test by Wako Pure Chemical Industries Pretest 3A determined that the amount of urinary protein was 300 mg / dl or more as a positive autoimmune condition. Ear dermatitis Observe the presence or absence of atopy-like dermatitis occurring in the ear area,
When dermatitis was observed, the autoimmune symptoms were positive. Hair loss When the hair loss on the face or back of the mouse was observed, it was defined as autoimmune symptom positive.

(2-3) Assay Method The appearance rate of mice with autoimmune symptoms in the control group and the incidence of mice with autoimmune symptoms in the sample administration group were tested by Fisher's exact probability calculation method.

(3) Test Results FIG. 1 shows the changes over time in the appearance rate of autoimmune symptoms in the mice of the sample administration group and the control group. There was no difference in the incidence of mice with autoimmune symptoms in the prednisolone group from the control group. The incidence of autoimmune symptoms in the ginseng yoeito dry extract powder administration group was significantly suppressed at 18 and 20 weeks of age compared to the control group. The combined use of Ninjinyoeito dry extract powder with prednisolone synergistically enhances the effect compared with the single administration of each, and the incidence of sick mice at all ages of 18 to 30 weeks is significantly higher than that of the control group. Suppressed From the above results, it is clear that the effect of prednisolone on suppressing the onset of autoimmune symptoms was enhanced by dried ginseng yoeito extract.

[Test Example 2] Acute toxicity test (1) Specimen and test method The ginseng yoeito extract powder of Example 1 was suspended in a 0.5 (W / V)% sodium carboxymethylcellulose aqueous solution (concentration: 1).
000 mg / ml) and ddY mouse (6 weeks old, weight 26-29)
g, 1 group 10 animals) orally at 10 g / kg, and after administration 2
The number of deaths up to a week was observed. (2) Test results No deaths were observed within 2 weeks after administration. Therefore, the drug of the present invention has extremely low toxicity.

[0020]

EXAMPLES Next, the present invention will be described more specifically with reference to examples. Example 1 Ginseng Yoei-to dry extract powder, 3.0 kg of ginseng, 4.0 kg of toki, ground yellow, white syrup, and peony, respectively
310 liters of water was added to a mixed crude drug consisting of peony, chin peel, distant each 2.0 kg, cinnamon 2.5 kg, yellow radish 1.5 kg, and schizandra licorice 1 kg each, and heated at 100 ° C. for 1 hour. . The extract is filtered, concentrated under reduced pressure to about 30 liters,
After spray drying, 6.7 kg of the title dry extract powder was obtained.

Example 2 Production of dried extract of Ginseng Yoeito Powder To the same mixed crude drug as in Example 1, 248 liters of ethanol / water mixed solvent [20:80 (V / V)] was added and heated under reflux for 30 minutes. And extracted. The extract was filtered and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure and pulverized to obtain 5.7 kg of dry extract powder.

Example 3 Production of fine granules (prescription) Main drug (dry extract powder of Example 1) 89.3 parts by weight Lactose 4.7 parts by weight Silica anhydrous 5.0 parts by weight Magnesium stearate 1.0 part by weight Part (Operation) The above components were thoroughly mixed, and the mixture was made into a plate-like material by a compression molding machine, pulverized and granulated with an oscillator, and rectified and sieved to obtain a fine granule containing 893 mg of the active ingredient in 1 g.

Example 4 Production of tablets (prescription) Main drug (dry extract powder of Example 1) 60 parts by weight Lactose 18 parts by weight Corn starch 5 parts by weight Synthetic aluminum silicate 9 parts by weight Carboxymethyl cellulose calcium 7 parts by weight Magnesium stearate 1 part by weight (operation) The above components were thoroughly mixed, and the mixture was tabletted into 300 mg tablets to give tablets each containing 180 mg of the active ingredient.

Example 5 Production of Capsule (Formulation) Main drug (dry extract powder of Example 1) 92.8 parts by weight Synthetic aluminum silicate 5.0 parts by weight Magnesium stearate 2.2 parts by weight (operation) Mix each component thoroughly and mix 36
Fill the capsule with 0 mg and fill the capsule with the main drug 334.
A capsule containing mg was obtained.

[Brief description of drawings]

FIG. 1 shows the test results using autoimmune disease model mice. The polygonal lines C, P, N and P + N respectively represent the following. Line C: Autoimmune symptom incidence rate of control mice Plot line P: Autoimmune symptom incidence rate of prednisolone-administered group line N: Ninjinyoeito dry extract powder administration group mouse autoimmune symptom incidence rate Line P + N: Prednisolone and carrot Occurrence rate of autoimmune symptoms in the group of mice administered with Yoei-to dry extract powder In addition, a significant difference test was performed on the incidence rate of autoimmune symptoms in the control group of mice by the assay method described in Test Example 1 (2-3). The results are shown by * mark or ** mark. * Mark P <0.05, ** mark P <
0.01

Claims (1)

[Claims] 1. An agent for enhancing the therapeutic effect of an adrenocortical hormone on an autoimmune disease, which contains Ninjinyoeito extract as an active ingredient.