JPH0216285B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel immunomodulator, particularly a therapeutic agent for rheumatoid arthritis.

In recent years, levamisole, D-penicillamine, and CCA [disodium N-(2-carboxyphenyl)-4-chloroanthranilate] have been used as immunomodulators.
Various compounds have been developed, but currently there are few that are fully satisfactory due to their strong toxicity to living organisms.

As a result of intensive research in view of these circumstances, the present inventor has developed the following formula (): The present invention has been completed based on the discovery that the trithiazole pentamethine cyanine compound represented by the formula is effective as an immunomodulator without toxicity or side effects, and particularly as a therapeutic agent for rheumatoid arthritis.

That is, the present invention relates to a therapeutic agent for rheumatoid arthritis containing a trithiazole pentamethine cyanine compound represented by the above formula () as an active ingredient.

A compound represented by formula (), i.e. 4,
4'-dimethyl-3,3'-di-n-heptyl-8-
[2-(4-Methyl-3-n-heptylthiazole)]-2,2'-dicarbocyanine diiodide is a well-known compound called platonin, and its pharmacological effects include antibacterial activity and promotion of wound healing. It is known to have effects such as activating reticuloendothelial hematopoietic organs and endocrine glands, and enhancing antibody production.

However, it has not been previously known that this compound has almost no toxicity or side effects, exhibits excellent immunomodulatory effects especially when administered orally, and is particularly useful as a therapeutic agent for rheumatoid arthritis. It was issued.

In other words, the compound represented by formula () exhibits an activating effect when the immune function is decreased for some reason, a suppressive effect when the immune function is enhanced, and a suppressive effect when the immune function is enhanced. It has the typical immunomodulatory effect of no effect.
On the other hand, it does not have the side effects of conventional immunomodulators, such as cytotoxicity such as granulocytopenia, vomiting, nausea, fever, skin rash, and myasthenia, but rather has the effect of maintaining normal cell function. In fact, it is an ideal immunomodulatory agent, making it possible to administer the drug continuously over a long period of time, and it has been found to be particularly effective against rheumatoid arthritis, an autoimmune disease.

Furthermore, it has been revealed that it exhibits excellent pharmacological effects, especially when administered orally, at a surprisingly small dose of 1/1000 to 1/10,000 of that of other immunomodulators. In addition to having almost no side effects, it was found to be an extremely easy-to-use drug compared to other immunomodulators. Since it is generally difficult for patients with rheumatoid arthritis to go to the hospital, oral administration is more preferable than in cases of other diseases.

Therefore, the drug of the present invention containing the above-mentioned compound as an active ingredient will greatly contribute as a therapeutic agent for rheumatoid arthritis.

The therapeutic agent for rheumatoid arthritis of the present invention is administered in an adult dose (active ingredient equivalent, hereinafter the same) from 10 to
A very small amount of about 500μg is enough to exert its effect. In particular, a dosage of 50 to 100 μg/1 to 2 days is preferred.

The therapeutic agent for rheumatoid arthritis of the present invention exhibits sufficient activity when administered orally, such as tablets, capsules,
It can be used as powder, granules, liquid, etc. It can also be used as nasal drops and suppositories. There are no particular restrictions on the preparation of the therapeutic agent for rheumatoid arthritis of the present invention, and the preparation may be carried out in a conventional manner using a commonly used carrier.

Next, the therapeutic agent for rheumatoid arthritis of the present invention will be explained with reference to Examples.

Example 1 [Pharmacological test] (1) Adjuvant arthritis suppressive effect 7-8 week old SD rats (approximately 150 g)
A suspension of Mycobacterium butyricum in liquid paraffin at a concentration of 12 mg/ml was injected intradermally into the right hind foot pad at a rate of 0.05 ml per rat. Adjuvant arthritis (AA) was induced. The volume of both hind paws was measured by the mercury exclusion method until 30 days after the adjuvant injection, and AA was evaluated.

(a) Preventive effect To examine the preventive effect of platonin on AA, administration of this drug was started at the same time as adjuvant administration, and oral administration was continued once a day until day 30. The results are shown in Figure 1. Similarly, FIG. 2 shows the results of administering D-penicillamine and levamisole instead of platonin.

As a result, platonin is 0.005 μg ~
It was found that AA was suppressed at a low dose of 0.05 μg/mouse, but that D-penicillamine and levamisole did not suppress AA even at a high dose of 1.5 mg/mouse.

(b) Therapeutic effect In order to examine the therapeutic effect of platonin on AA, administration of this drug was started on the 14th day after administration of the adjuvant and continued orally once a day until the 40th day. A similar experiment was conducted using hydrocortisone as a comparative drug. The results are shown in Figure 3.

As a result, platonin is 0.005 μg ~
Platonin was suppressed at a low dose of 0.05 μg/animal, but no suppressive effect was observed with higher doses of platonin, indicating that there is an optimal dose.

(2) Effect on carrageenan-induced inflammation
Used in groups of 5 animals, 0.1ml of 1% carrageenan suspension
Injected intradermally into the footpad of the right hind leg, and the volume of the injected leg was measured using the mercury exclusion method over the next 6 hours.
This was used to evaluate carrageenan-induced inflammation.

Platonin was administered orally 30 minutes before carrageenan suspension injection. The results are shown in Figure 4. As a result, no carrageenan-induced anti-inflammatory effect could be observed at doses of 0.005 μg to 0.05 μg/mouse of platonin. Therefore, the pharmacological effects of platonin are thought to be expressed through immunomodulatory effects rather than anti-inflammatory effects.

(3) Body weight change On day 1, day 10, during the test period for the preventive effect of the adjuvant arthritis inhibitory effect in (1)(a) above,
The weight of each rat was measured on the 20th and 30th day. The results are shown in FIGS. 5 and 6. As a result, no difference was observed in the body weight changes of rats treated with D-penicillamine and levamisole compared to controls, but 0.05 μg to 0.5 μg of platonin was administered to rats.
Despite the decrease in foot swelling when administered to animals,
A clear increase in body weight change was observed in the rats compared to the control, and a marked improvement in systemic symptoms was also observed.

(4) Acute toxicity Male Wistar rat (approximately 150g)
Using a group of 8 animals, platonin suspended in 5% gum arabic solution was administered intraperitoneally and orally using a gastric probe, observed for 7 days to determine the number of deaths, and the LD ₅₀ value was determined by the van der Wuerden method. I asked for it. As a result, the _LD50 value for intraperitoneal administration was 54
mg/Kg, and the LD ₅₀ value for oral administration is 1.5g/Kg.
It was hot. Considering that this drug is effective at 0.005 μg to 0.05 μg/animal in the above-mentioned adjuvant arthritis suppressive effect, it can be seen that this compound has an extremely wide safety margin.

Example 2 [Clinical case] (1) Case 1 A patient with multiple rheumatoid arthritis who developed symptoms 3 years ago and has severe pain in the right hip joint, whose condition does not change even after injecting 25 mg of Thiozol (registered trademark) twice a week. When a 47-year-old patient was given 50 μg of platonin once a day on an empty stomach, his morning stiffness and general fatigue improved from the 5th day, the inflammation in his wrist joints disappeared, and his pain almost disappeared. By the morning of the 7th day, I was able to get up and go down the stairs with great ease. No side effects were observed.

(2) Case 2 The disease developed 8 years ago, and despite the use of Thiozol (registered trademark) and indomethacin (registered trademark) suppositories, it continued to worsen, and the side effects of the medicines included stomach ulcers, acne, and diarrhea, causing pain every day. Patients with multiple rheumatoid arthritis, who continue to suffer from rheumatoid arthritis and are on crutches.
When 100 μg of platonin was administered orally once a day on an empty stomach to a 57-year-old patient, general fatigue and morning stiffness improved from the third day. From the 5th day onwards, the inflammation in the joints decreased and indomethacin suppositories were no longer needed.
I've started sleeping better. From day 7, platonin was administered orally twice a week. From the 3rd week onwards, the swelling in the joints (water accumulation) improved and he was able to walk again.
No side effects were observed.

Example 3 Using platonin as an active ingredient, the following various formulations of therapeutic agents for rheumatoid arthritis were prepared.

(1) Tablets Tablets with the following formulation were prepared by a conventional method.

Ingredients mg/tablet Active ingredient 0.05 Lactose 79.95 Cornstarch 62.50 Sucrose fatty acid ester 7.50 Total 150 In the case of gastrosoluble agents, a 5% by weight coating of To-5 was applied, followed by sugar coating. In the case of enteric-coated agents, a 10% by weight coating of HP-55 was applied, followed by sugar coating.

(2) Capsules Capsules with the following formulation were prepared by a conventional method.

Ingredients mg/capsule Active ingredient 0.05 Lactose 146.95 Sucrose fatty acid ester 3.00 Total 150 (3) Powder A powder having the following formulation was prepared by a conventional method.

Ingredients mg Active ingredient 0.05 Lactose 499.95 Total 500 (4) Suppositories Suppositories with the following two formulations were prepared using conventional methods.

Suppository A Ingredient mg/active ingredient 0.05 PEG#1000 1440 PEG#4000 59.95 Total 1500 Suppository B Ingredient mg/active ingredient 0.05 Witepsol H-15 1280 Witepsol E-85 319.95 Total 1600 (5) Syrup Next Prescription syrup (1 dose:
50 μg/5 ml) was prepared by a conventional method.

Ingredients Content/100ml Active ingredient 1mg 60g sugar Glycerin 10g Sodium citrate 0.1g Sodium benzoate 0.3g Satucalin sodium 0.1g Purified water appropriate amount

[Brief explanation of drawings]

Figure 1 is a graph showing the preventive effect of platonin on adjuvant arthritis in rats.
The figure is a graph showing the preventive effect of D-penicillamine and levamisole on adjuvant arthritis in rats. Figure 3 is a graph showing the therapeutic effect of platonin on adjuvant arthritis in rats. Figure 4 is a graph showing the effect of platonin on carrageenan-induced inflammation in rats. Figure 5 is a graph showing the effect of platonin on the body weight of rats with adjuvant arthritis, and Figure 6 is D.
- is a graph showing the effects of penicillamine and levamisole on the body weight of rats with adjuvant arthritis.

Claims (1)

[Claims] 1 Formula (): A therapeutic agent for rheumatoid arthritis containing a trithiazole pentamethine cyanine compound represented by the following as an active ingredient. 2 Claim 1 in which the dosage form is an oral dosage form
A therapeutic agent for chronic rheumatoid arthritis as described in .