JPS5869813A - Serum lipid depressant - Google Patents

Abstract

PURPOSE:To provide the titled agent effective to depress the lipid level in blood and having high safety, by using pantetheine-S-sulfonic acid or its salt as an active component. CONSTITUTION:Pantetheine-S-sulfonic acid of formula separated from Panax ginseng, or its alkali metal salt or alkaline earth metal salt is used as an active component of the drug. The compound of formula which is a precursor of coenzyme A in the body, has the activity of depressing the serum lipid level and the preventive activity to an animal affected by Triton hyperlipemia. Since the compound of formula is white crystalline powder in contrast with an analogous compound, pantethine, it can be handled easily, and has little bitter taste. Administered orally or parenterally at a dose of 100-1,000mg/day, usually 300- 500mg/day. Its preventive effect has been demonstrated by the fact that the lowering tendency of the cholesterol and triglyceride is more remarkable in the preadministered group than the group administered only once.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel serum lipid-lowering agent, more specifically, /l! The present invention relates to a serum lipid-lowering agent containing 7-8-sulfo/acid or a salt thereof as an active ingredient.

The present inventors conducted various studies on sulfonic acid group-containing compounds focusing on the in vivo physiological activity of sulfonic acid groups, and found that pantethine-8-sulfonic acid, an extract from a natural product, was discovered that it has a serum lipid-lowering effect and a preventive effect on hemorrhagic animals;
Based on this new knowledge, the present invention was completed.

The active ingredient of the present invention, nozontetheine=8-sulfo/acid, is a known compound represented by the formula [I], CH,' HOCH,CCH(OH) C0NHCH,CH,C0
NHCH,CH,880,Hc)(,CI)2/Zine (Chem.

Pharm, Bull, Vol 22(7), 16
52-1638.1974). This compound is a naturally occurring, non-toxic and safe compound, but recently D-
It has become possible to produce it industrially advantageously from pantothenic acid and 2-aminoethanethiol sulfuric acid, and a production method with perfect yield and purity has been developed (Japanese Unexamined Patent Publication No. 1983
19061). Although this compound has been proven to be the active substance of coenzyme A in living organisms (Japan).

J, Microhiol, Vol 16(5), 2
59-242.1972), there has been no knowledge that it has the effect of lowering blood lipids.

Panchiti y-8-sulfonic acid has an extremely excellent serum lipid-lowering effect, and can also be expected to have a preventive effect, as is clear from the test examples described later. Furthermore, since this substance is isolated from carrots and is a natural product, there is no problem at all from the viewpoint of safety and toxicity, and the results of toxicity tests in rat NC indicate that the LD for oral administration is 10. f/kl1 or higher, and was proven to be substantially non-toxic. Moreover, this substance is easy to handle and formulate, and is thus found to be extremely excellent as a medicine in all respects.

In the present invention, not only the free acid represented by formula CI) but also its salt can be advantageously used as an active ingredient. Examples of the salt include organic salts such as amine salts and pyridinium salts, as well as inorganic salts such as alkali metal salts and alkaline earth metal salts, with calcium salts being particularly preferred.

Pantethine is known as a related compound of banchiti/-8-sulfonic acid, but this substance is an amorphous viscous substance that is inconvenient to handle and has a strong bitter taste when administered orally. present. On the other hand, pantetin-8
- Sulfonic acid is a white powdery crystalline substance that can be filtered and has almost no bitter taste. In addition, there is one pa/tetei/ used in the present invention.
-8-sulfonic acid is /I! /so/teteine-8-sulfonic acid has a remarkable effect of reducing serum triglycerides compared to ntetine, and also has a remarkable effect of significantly reducing diarrheal symptoms, which is the main side effect of pantethine. be.

The serum lipid-lowering agent of the present invention can be administered either orally or parenterally.7 In the case of oral administration, soft and
It can be administered in the form of hard capsules or tablets, granules, fine granules, or powders.For parenteral administration, it can also be administered in the form of injections, drips, and in some cases, suppositories. can.

When administering the active ingredient according to the present invention to humans, the dosage varies depending on the symptoms and drug mrc, but the dosage is 100 mg/day.
0 to 1000 da is suitable, 1 usually 500 to 500 m
It is preferable to set it to 9.

K for formulating the active ingredient of the present invention is prepared according to a conventional method.
Surfactants, excipients, lubricants, flavoring agents, flavoring agents 1 Coloring agents, flavoring agents, preservatives, suspending agents, wetting agents, film-forming substances, coating aids, and other adjuvants are used as appropriate.

Next, a test method for confirming the lipid-lowering activity of the above compound CI] will be described.

Test animal weighs 180? A certain male rat (manufactured by Tokyo Experimental Animals Co., Ltd.) was used; the rats were a control group (normal model), a Triton control group (hyperlipidemia model),
Triton-nontetheine co-administration group, Triton-nontetheine-8-sulfonic acid co-administration group, Triton-
Pantethine dosing %, dry/-pantethine-8
- Divide into 6 groups including sulfonic acid pre-administration group, and use 10 animals per group. The feed was commercially available solid feed (rcl-2 manufactured by Nippon Talea Co., Ltd.).
J), tap water was used as drinking water, and the drug was dissolved at a ratio of 200 Da in [19-1-1] of saline, and Triton WR-1339 was dissolved in α9-111 of saline.
It was used by dissolving it in a ratio of 7 to 100.

The control group received A91 saline once a day at 11:00 a.m.
The rats were orally administered at a dose of al/kg for one week, and fed for 6 hours after the final administration. Afterwards, the rats were anesthetized with ether and blood was collected from the heart. [7] Serum lipids were analyzed according to a conventional method.

The Dryde 71 control group was orally administered with 91 saline at a dose of 5111/9) once a day at 11 a.m. KQ, and at the same time as the final administration of Triton WR-1559,
400 da/yu was injected into the common vein. Fasting was started after the injection, and 5 d of blood was collected from the heart under ether anesthesia 6 hours later.
Serum lipids were analyzed according to standard methods. For the dryide/nontechine co-administration group, pantethine solution was orally administered once at 11:00 am at 1000 m9/kJ, and at the same time as the administration.
Triton WR-151,400 da/yu was injected into the common vein. After the injection, fasting was started, and after 6 hours, 5 m of blood was collected from the heart under ether anesthesia, and 5 jL of serum fat was collected according to the standard method.
was analyzed. In the tritone-panctitiy-8-sulfonic acid co-administration group, pantetin-8 was administered at 1w111 p.m.
- Sulfonic acid solution was administered orally once to 1000 m9/9, and at the same time Triton WR-1359, ao
It was injected from the oiv/yuto common vein. Fasting was started after the injection, and blood was collected from the heart under ether anesthesia 6 hours later, and serum lipids were analyzed according to standard methods. To the Triton-/Zonetech/approx. administration group, Pantethine solution was orally administered once a day at 10,001v/kp for one week at 11am, and at the same time as the final administration, Triton WR-1539,40
0 Da/Yu was injected into the general vein.

After 6 hours, blood was collected from the heart under ether anesthesia and serum lipids were analyzed according to a conventional method. For the group pre-administered with tritonoguntetheine-8-sulfonic acid, one dose of pantetheine-8-sulfonic acid solution was administered at 11 a.m.
Orally administered once a day at a rate of 9 in 1000 da/day for one week, and at the same time as the final administration, Triton WR-1359,40
0 da/yu was injected into the common vein. After injection, fasting was started, and 6 hours later, 5Wll of blood was collected from the heart under ether anesthesia and serum lipids were analyzed according to standard methods. Analysis of serum lipids was performed by the following method.

Triglyceride: Enzyme method (Triglyceride Test Wako) Cholesterol: lll method Cholesterol C
- Test Wako) The results are shown in Table 1.

Table 1 Reduction rate for Triton-control group was significantly (P<0.
001) Increases serum cholesterol and triglyceride levels, indicating the creation of a hyperlipidemic animal model. Triton-Pantetin-8 for hyperlipidemic animals
- Sulfonic acid has the effect of significantly reducing cholesterol levels and triglyceride levels compared to nozontetin. In addition, the cholesterol and triglyceride levels tended to be slightly lower in the pre-administered group than in the multiple-administration group, and it is well established that pantethine-8-sulfonic acid has a preventive effect on increasing serum lipids. Ta.

In addition, during this study, the diarrheal symptoms were severe in the pantethine pre-administration group (9 out of 10 animals showed diarrheal symptoms, one of which died on the 6th day of administration). In the sulfonic acid pre-administration group, only 1 out of 10 animals showed diarrhea symptoms, and the results showed that pantetin-8
- Sulfonic acid is more effective than pantethine in lowering serum lipids and preventing increases in serum lipids, and it has been found to be extremely safe, with significant reductions in side effects, especially diarrheal symptoms.

Examples of the present invention are shown below.

Example t 500 q of nozontetheine-S-sulfonic acid was mixed and stirred with 5 t of powdered glucose, and this was aseptically distributed into vials, sealed, sealed with nitrogen gas, and stored in a cool, dark place. - Physiological saline 500 - is added to prepare the solution. This is used as an intravenous injection or drip depending on the symptoms.

Example 2 50 t of powdered glucose was added to 509 pantethine-8-sulfonic acid, 99 t of lactose, 1 t of hydroxypropyl cellulose and 2 t of magnesium stearate were weighed out, and these were also thoroughly mixed and processed with a tablet machine to make an adult tablet. 1000 tablets were made.

Agent Patent Attorney 1) Parent Male

Claims (1)

[Scope of Claims] A serum lipid lowering agent containing t/Z nteteine-8-sulfonic acid as an active ingredient. Z. The serum lipid-lowering agent according to claim 1, wherein the active ingredient is a pan-alkaline salt or a pan-alkaline earth salt of α-8-sulfonic acid.