JPH0672870A - Antiulcer agent - Google Patents

Abstract

PURPOSE:To obtain a low toxic antiulcer agent, comprising nobiletin as an active ingredient and excellent in safety and therapeutic effects. CONSTITUTION:The objective antiulcer agent comprises nobiletin expressed by the formula as an active ingredient. Furthermore, the daily dose of this antiulcer agent for an adult is 0.2-20mg/kg, expressed in terms of the nobiletin and preferably administered once or in 2 to 3 divided portions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an anti-ulcer agent. More specifically, the formula (I)

[0002]

[Chemical 1] The present invention relates to an antiulcer agent containing nobiletin as an active ingredient.

[0003]

2. Description of the Related Art Many drugs are used as antiulcer drugs having a defense factor enhancing action. For example, sucralfate is a typical antiulcer drug with enhanced defense factor and is widely applied clinically.

Among Chinese herbal medicines, those having an anti-ulcer effect like Daisaikoto are known [Japanese Journal of Pharmacology, 91, 3].
19 (1988)]. In addition, Minami, which is mixed with Daisaikoto, is used as a stomach medicine [THE KAMPO, 8 (4), 104 (1990)]. On the other hand, nobiletin has the formula (I)

[0005]

[Chemical 1] It is a compound represented by, and is a seed (Citrus nobilis Lo
ur) has been reported [J. Chem. So
c., 1008 (1938)]. In addition, a synthetic report has been made (Pharmaceutical Journal, 60, 614-615, 1940). Nobiletin is cycli
It has been confirmed that it exhibits a c AMP phosphodiesterase inhibitory action [Planta Med., 46, 162 (1982)], but its antiulcer action is not known at all.

[0006]

An object of the present invention is to provide a novel antiulcer agent.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted various studies on the components of chum nut, and as a result, have found that nobiletin is contained in chum nut and that nobiletin has an excellent anti-ulcer action. completed. The anti-ulcer agent of the present invention is easily produced by formulating an extract fraction from nobiletin or a crude drug containing nobiletin (for example, a pot or a nutberry) by a conventional method.

For example, tablets, granules, fine granules or powders are prepared by adding nobiletin to usual pharmaceutical additives such as excipients such as lactose, glucose and mannitol, lubricants such as magnesium stearate, sodium alginate and hydroxy. It is produced by a conventional method by mixing with a binder such as propyl cellulose, corn starch, starch or the like or a disintegrating agent such as carboxymethyl cellulose, crystalline cellulose or the like.

The antiulcer agent of the present invention containing nobiletin as an active ingredient is preferably orally administered to humans. The dose varies depending on the patient's condition, age, etc., but is usually 0.2 to 20 mg / k per day for adults as nobiletin.
It is preferable to administer g orally once or in 2 to 3 divided doses.

[0010]

INDUSTRIAL APPLICABILITY Nobiletin showed a far stronger anti-ulcer effect than sucralfate as a control compound in a test for measuring the inhibition rate of the length of damage caused in gastric mucosa by 99.5% ethanol (test described later). See Example 1). On the other hand, the toxicity of nobiletin is low (see Test Example 2 below). Therefore, the drug of the present invention containing nobiletin as an active ingredient is useful as a highly safe antiulcer drug. The effects of the present invention will be described in more detail below with reference to test examples. [Test Example 1] Anti-ulcer test (1) Test compound Nobiletin sucralfate (control compound)

(2) Test method Robert et al. [Gastroenterology, 77, 433]
(1979)], and Wistar ST male rats (170
(-200 g) was fasted for 24 hours, and then the control group rats were orally administered with the 5% acacia solution alone, and the test compound administration group rats were orally administered with the test compound suspended in the 5% acacia solution (dosage volume). 5 ml / kg). Thirty minutes later, 1 ml of 99.5% ethanol was orally administered to each rat, and one hour after the administration of ethanol, the stomach was excised under urethane anesthesia. After injecting 10 ml of 1% formalin solution into the excised stomach, it was immersed in 1% formalin solution for 10 minutes. Next, an incision was made along the bay, and the length (mm) of the damage that had occurred in the glandular stomach was measured under a stereoscopic microscope, and the total was taken as the ulcer index. The inhibition rate was calculated from the average value of the ulcer index of the test compound administration group and the average value of the ulcer index of the control group. (3) Test Results The ED ₅₀ value was calculated from the dose of the test compound and its inhibition rate (Table 1).

[0012]

[Table 1]

[Test Example 2] Acute toxicity test (1) Test compound Nobiletin (2) Test method After acclimatizing a ddY male mouse (5 weeks old) for 1 week in an animal room,
After fasting for 24 hours, nobiletin was suspended in a 5% gum arabic solution and orally administered (administration volume: 20 ml / kg). (3) Test results Even when a dose of 1000 mg / kg of nobiletin was administered to mice, there were no deaths and no abnormal symptoms were observed. Therefore, the toxicity of nobiletin is low.

[0014]

EXAMPLES The present invention will be described with reference to Examples and Reference Examples. Example 1 (production of granules)

[0015]

[Table 2]

Nobiletin was mixed with an equal amount of potato starch and the mixture was ground. The remaining potato starch, lactose and hydroxypropyl cellulose were added thereto and mixed uniformly, granulated according to a usual method and then sized to obtain a granule containing 100 mg of nobiletin in 1 g. Example 2 (Production of tablets)

[0017]

[Table 3]

Mix nobiletin and potato starch well,
Then, water was added and the mixture was kneaded and passed through a screen having a mesh of 1 mm × 1 mm to form a granule. No.1 after drying
After sizing with a 6-mesh (BS) sieve and mixing lactose and magnesium stearate, 1 tablet 200
The tablets were compressed into mg to give tablets each containing 100 mg of nobiletin. Example 3 (Production of capsule)

[0019]

[Table 4] The above components were uniformly mixed and 300 mg each of the mixture was filled in a No. 2 hard capsule to obtain a capsule containing 100 mg of nobiletin in each capsule.

Reference Example 1 10 kg of hot water was added to 18 kg of dry powder of Gumami (produced in Jiangxi Province, China) and extracted for 1 hour. The extract was concentrated under reduced pressure to 37.8
A concentrated liquid of kg was obtained. The concentrated solution was partitioned with a mixed solution of methylene chloride-methanol-water (2: 1: 1), and the lower layer was concentrated under reduced pressure and then freeze-dried to obtain 112.5 g of fraction A.

Of the fraction A, 94.9 g of methylene chloride
Partitioning was performed with 5000 ml of a mixture of methanol-water (2: 2: 1), the lower layer was concentrated under reduced pressure, and then degreased with hexane to obtain 69.8 g of a fraction B. Of this fraction B, 10.0 g was purified by high performance liquid chromatography (preparation condition), and the fraction eluted at 69 to 74 minutes was collected. Subsequently, the product was purified again by high performance liquid chromatography (preparative conditions), and the fraction eluted around 68 minutes was collected to obtain 302 mg of a compound. H-NM of this compound
R and ¹³ C-NMR measurements are reported in the literature [Chem. Pharm. Bull., 3
7 (4), 1092 (1989)].

Preparative conditions Column: YMC-ODS, 50φ × 500 mm Mobile phase: 60% Methanol-water Flow rate: 48 ml / min Temperature: Room temperature Preparative conditions Column: YMC-ODS, 50φ × 500 mm Mobile phase: 45% Acetonitrile-water Flow rate: 48 ml / min Temperature: Room temperature

Claims (1)

[Claims] 1. An anti-ulcer agent containing nobiletin as an active ingredient.