JPH06293653A - Antirheumatic agent - Google Patents

Abstract

PURPOSE:To obtain an antirheumatic agent having high pharmacological effect and low side action by using SAIREITO (a kind of blended Chinese herb drugs) as an active component. CONSTITUTION:SAIREITO composed of 4-7 pts. of SAIKO (root of Bupleurum falcatum), 5-6 pts of TAKUSHA (bulb of Alisma plantago-aquatica), 4-5 pts. of HANGE (rhizome of Pinellia ternata), 3 pts. of OUGON (root of Scutellaria baicalensis), 3-4.5 pts. of SOUJUTSU (rhizome of Atractylodes lancea), 2-3 pts. of DAISOU (fruit of Zizyphus jujuba), 3-4.5 pts. of CHOREI (sclerotium of Polyporus umbellatus), 2-3 pts. of NINJIN (rhizome of Panax ginseng), 3-4.5 pts. of BUKURYO (sclerotium of Poria cocos), 2 pts. of KANZOU (root of Glycyrrhiza glabra), 2-3 pts. of KEIHI (bark of Cinnamomum cassia) and 1-4 pts. of SHOUKYOU (rhizome of Zingiber officinale) is used as it is or the extract SAIREITO is used as an active component. The agent is prepared in the form of peroral drug or a parenteral drug such as injection and drip. The daily dose of the agent is 1-10g (in terms of dried extract of the SAIREITO) for adult in 1-3 divided doses in the case of peroral administration. The SAIREITO extract can be prepared by extracting the SAIREITO having the above composition with 10-20 times volume of hot water and filtering the extracted solution.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a drug useful as an antirheumatic agent.

[0002]

BACKGROUND ART In recent years, various anti-rheumatic drugs have been developed for rheumatoid arthritis, but none of them can completely suppress the progression of rheumatoid arthritis, and steroidal anti-inflammatory drugs have serious side effects. Many have. Therefore, an experiment of rheumatoid arthritis using a combination of a steroidal or non-steroidal anti-inflammatory drug that has been often used as an anti-inflammatory agent and a Kampo medicine has been conducted. Report of alleviation of side effects of Chinese medicines (Chinese medicine vol.9, No.316-20,1985, Japanese and Chinese Medicine Society 5 444-445,1988, Japanese and Chinese Medicine 5 480-481,1988)
Has been done. In addition, although an experiment on an adjuvant arthritis model using Sairei-to alone has also been conducted, the experiment on the adjuvant arthritis model is considered to be different from the model for rheumatoid arthritis. It did not give any suggestion about the rheumatic effect.

As a disease model of rheumatoid arthritis,
Adjuvant arthritis and collagen arthritis produced by injecting Freund's complete adjuvant are known. The reason that adjuvant arthritis is said to be a model close to Reiter's syndrome among these disease models is that adjuvant arthritis exhibits not only polyarthritis but also associated symptoms in skin mucous membranes and various organs. On the other hand, collagen arthritis is said to be a model closer to rheumatoid arthritis because it does not have associated symptoms like the adjuvant arthritis model, and is used for elucidating the pathological condition of rheumatoid arthritis.

[0004]

The steroidal or non-steroidal drugs which have been widely used as anti-inflammatory agents have a serious problem that they are accompanied by side effects. Therefore, anti-rheumatic drugs with few side effects and high pharmacological effects are present. The development of agents was desired.

[0005]

[Means for Solving the Problems] As a result of intensive investigations by the present inventors to find an anti-rheumatic drug with few side effects and high pharmacological effects, an anti-rheumatic drug containing Saireito as an active ingredient is desired. As a result, they found that the usefulness was extremely high, and completed the present invention.

That is, the present invention provides an anti-rheumatic agent containing Sairei-to as an active ingredient.

Saireito, which is the active ingredient 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.

The composition ratio of this Sairei-to is determined according to the classical Chinese herbs, but the classical Chinese herbs vary in the ratio of the constituent herbal medicines, and the natural herbs are dependent on the natural conditions such as the place of origin, the time of collection and the 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

The anti-rheumatic agent of the present invention may be formulated by using Sairei-to in the above blending ratio as it is or by using an extract thereof as an active ingredient and combining this with a known pharmaceutical carrier.

Examples of the Sairei-to extract include various water-based solvent extracts of Sairei-to, and it is preferable to use the water extract.

As a concrete example of preparation of Sairei-to extract,
A method of extracting Sairei-to having a composition in the above range with hot water in an amount of 10 to 20 times, preferably 12 times, and filtering the resulting extract is mentioned. This extract can be dried as necessary to give a dry powder.

The anti-rheumatic drug of the present invention can be administered either as an oral drug or a parenteral drug such as an injection or an infusion.

The pharmaceutical carrier can be selected according to the above-mentioned administration form and dosage form. In the case of oral preparations, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like are used. It When preparing an oral preparation, a binder, a disintegrant,
Surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents,
Fragrances and the like can be added. Specific examples thereof include the following.

(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, 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 compounds of the present invention can also be administered as oral liquid preparations such as suspensions, emulsions, syrups and elixirs.
A flavoring agent and a coloring agent can be added.

On the other hand, in the case of a parenteral preparation, it is manufactured according to 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 and the like 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, if necessary, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like can be appropriately added.

The dose of this anti-rheumatic drug depends on the route of administration,
Although it varies depending on the degree of disease, age of recipient, etc., in general, in the case of oral administration, an adult daily amount of Saireito dry extract is about 1 to 10 g and may be administered in 1 to 3 divided doses. .

The Sairei-to used in the present invention has a long history as a Chinese medicine and its safety has been confirmed, so that it can be used with confidence. For example, the oral administration of 15 g / kg, which is the administration limit, to mice and rats is extremely safe, as no deaths or abnormal findings are observed.

The present invention will be described in more detail with reference to specific examples, formulation examples and experimental examples, but the present invention is not limited to these specific examples, formulation examples and experimental examples.

[Specific Example 1] Saiko 7g, Sawaraki 5g, Half-summer 5g, Yellow rice 3g, Soyaku 3g, Oomu 3g, Boar 3g, Ginseng 3g, Ginseng 3g, Licorice
To 2g, cinnamon bark 2g, and ginger 1g, add 12 times the amount of purified water.
Extract for about 0 minutes, perform solid-liquid separation, and obtain the separated liquid for 2 minutes
The concentrate was concentrated to 1 volume, and the concentrate was spray-dried to obtain a dried extract.

[Formulation Example 1] Preparation of granules: 200 g of the dry extract powder of Sairei-to prepared in Example 1 was mixed with 89 g of lactose and 1 part of magnesium stearate.
After mixing with g, the mixture was compressed with a single-shot tableting machine to obtain a slug tablet having a diameter of 20 mm and a weight of about 2.3 g. This slug tablet is crushed with an oscillator, sized and sieved to give a particle size of 20-50.
A granule of mesh was obtained.

[Formulation Example 2] Preparation of tablets: 200 mg of the dry extract powder prepared in Example 1 was added to 20 g of microcrystalline cellulose and 5 g of magnesium stearate.
The mixture is mixed with
A tablet having a size of 7 mm and a weight of 225 mg was produced. In this tablet 1 tablet,
Contains 200mg of dry extract powder of Sairei-to.

[Formulation Example 3] Preparation of capsules: Hard capsules were filled with 500 mg of the dry extract powder prepared in Example 1 to prepare capsules.

[Experimental Example 1] (Material and method) As the animal, a 6-week-old mouse of DBA / 1 (CLEA Japan) strain was used. The method of inducing arthritis is as follows: bovine-derived type II collagen dissolved in 0.05 N acetic acid was used in an equal amount of Freund's (F
reund) as a water-in-oil type emulsion mixed with 100 μg intradermally in the ridge, and after 3 weeks, the same amount of I
A booster with type I collagen was given to the same area. The number of mice used in the experiment was 12 in each group, and the measurement was performed 4 weeks after the first immunization. The administered Sairei-to was mixed in the diet so that the daily intake was the amount described below. The experimental group is
Divided into 6 groups and 9 groups. (I) Untreated group (II) a. Saireito 100 mg / kg / day administered 1 week before the first immunization b. Saireito 100 mg / kg / day administered after the booster immunization (III) a. Saireito 500 mg / kg / day administered 1 week before the initial immunization b. Saireito 500 mg / kg / day administered after the additional immunization (IV) a. Saireito 1500 mg / kg / Day 1 week prior to the initial immunization b. Sairei-to 1500 mg / kg / day post-immunization (V) Dexamethasone 1 mg / kg intraperitoneal injection once weekly (VI) Dexamethasone 1 mg / kg booster group administered 3 times a week

The onset of arthritis was evaluated by the arthritis incidence and arthritis onset score.

The arthritis incidence (%) was calculated by the following formula. The results are shown in FIGS.

The arthritis onset score was calculated by the following formula based on the score evaluated randomly by the same examiner for each limb according to the following criteria. The results are shown in FIGS. No change 0 With mild swelling 1 With moderate swelling and redness 2 With significant swelling and redness 3 With bone changes 4

For the anti-collagen antibody titer, the ELISA method (En
Using a enzyme-linked immunosorbent assay (zyme-linked immunosorbent assay), bovine-derived type II collagen was prepared at 10 μg / ml, and 1 μg of each type was coated on each well of the flat bottom plate. After washing with PBS (Phosphate Buffered Saline) + Tween 20, BSA (Bov
in Serum Albumin; bovine serum albumin), and mouse serum was diluted 2000 times and reacted. Then, peroxidase-labeled rabbit anti-mouse IgG (Immunogl
After adding obulin G), ABTS [2, azino-bis (3-ethylbenzthia
zoline-6-sulfonic acid)] is used to develop color, and OD (Opti
cal Density; measured at 415 nm. The result is shown in Figure 8.
~ As shown in FIG.

(Results) 1. Arthritis incidence (FIGS. 1 to 3) In the arthritis incidence, the most effect was observed in the administration group of 500 mg / kg / day, and the incidence was almost 100% in the control group at 7 weeks. However, it was below 50% in the administration group. 1
Regarding the 00 mg and 1500 mg groups, although there were differences in the early stage of onset, the onset was almost the same at 9 to 10 weeks. In the dexamethasone 1 mg / kg / weekly group, the onset was not suppressed at all compared to the control group. The group administered three times a week showed a marked effect.

2. Arthritis development score (FIGS. 4 to 7) 100, 500, 1500 mg / kg / da at any time during the observation period
In each of the groups before and after y, the onset score of the administration group was lower than that of the control group (FIGS. 4 to 6). The dexamethasone once-weekly group had almost the same onset score as those of the Sairei-to group. However, in the group administered three times a week,
A remarkable inhibitory effect on collagen arthritis was recognized. There was no difference between the pre-immunization group and the post-immunization group in any of the groups, and it seems that the effect can be expected if the administration is performed early after the onset. The doses of Sairei-to administered after immunization were compared in Fig. 7, and there seems to be almost no difference in efficacy among the three groups. From the above, it is considered that the administration of Sairei-to from the onset score suppresses the onset of collagen arthritis, and its effect is comparable to that of dexamethasone 1 mg / kg / week.

3. Anti-collagen antibody titer (FIGS. 8 to 11) The anti-collagen antibody titer in the 500 mg / kg / day group was lower than that in the control group even before and after administration. The antibody titer in the 100 mg / kg / day group also tended to be lower than that in the control group. There was no difference in the 1500 mg / kg / day group compared to the control group.

Once a week for the dexamethasone administration group,
The antibody titer was significantly lowered in both of the three times weekly administration groups.

From the above-mentioned results, it was found that Sairei-to delays the onset of collagen arthritis and ameliorate it. It was also found that the effect was almost unchanged after administration of Sairei-to before or after immunization with type II collagen.

[0038]

[Brief description of drawings]

FIG. 1 shows the results of experiments on the incidence of arthritis.

FIG. 2 shows the experimental results of arthritis incidence.

FIG. 3 shows the experimental results of arthritis incidence.

FIG. 4 shows the experimental results of arthritis onset score.

FIG. 5 shows the experimental results of arthritis onset score.

FIG. 6 shows the experimental results of arthritis development scores.

FIG. 7 shows the experimental results of arthritis score.

FIG. 8 shows the experimental results of anti-collagen antibody titer.

FIG. 9 shows the experimental results of anti-collagen antibody titer.

FIG. 10 shows the experimental results of anti-collagen antibody titer.

FIG. 11 shows the experimental results of anti-collagen antibody titer.

[Explanation of symbols]

The polygonal lines in FIGS. 1 to 11 have the following meanings. Broken line CIA: shows the result of the experimental group (I). Fold line Dex1: shows the results of the experimental group (V). Broken line Dex3: shows the result of the experimental group (VI). Broken line PR. 100: shows the result of the experimental group [(II) -a]. Polygon PO. 100: shows the result of the experimental group [(II) -b]. Broken line PR. 500: Shows the results of the experimental group [(III) -a]. Polygon PO. 500: Shows the results of the above experimental group [(III) -b]. Broken line PR. 1500: shows the result of the above experimental group [(IV) -a]. Polygon PO. 1500: shows the result of the above experimental group [(IV) -b].

[Procedure amendment]

[Submission date] April 7, 1994

[Procedure 3]

[Document name to be corrected] Drawing

[Correction target item name] All drawings

[Correction method] Change

[Correction content]

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FIG. 11

Claims (1)

[Claims] 1. An antirheumatic agent containing Saireito as an active ingredient.