JPS6372625A - Blood platelet agglutination inhibitor - Google Patents

Abstract

PURPOSE:To obtain a blood platelet agglutination inhibitor, containing (6)- shogaol obtained from a dried rhizome of ginger as an active ingredient and useful for treating cerebral infarction, cerebral thrombosis, arteriosclerosis, angina pectoris, etc. CONSTITUTION:A blood platelet agglutination inhibitor obtained by extracting a dried rhizome of ginger with ether, etc., to give an extract essence, subjecting the resultant extract essence to column chromatography using silica gel as a solid support, carrying out development with a solvent, e.g. n-hexane, etc., to give (6)-shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one] expressed by the formula and formulating the resultant shogaol as an active ingredient into an oral agent, e.g. tablet, capsule, granule, etc., or parenteral agent, e.g. injection suppository, etc. The dose thereof for adults is up to 3 times a day based on 20-80mg at a time as an oral agent and 0.25-10mg a month as a parenteral agent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a platelet aggregation inhibitor containing (6)-shogaol as an active ingredient.

[Conventional technology and problems] The present invention relates to a platelet aggregation inhibitor.

In recent years, with changes in dietary habits and aging of the population in Japan, the rapid increase in thrombotic diseases such as myocardial infarction and cerebral thrombosis has become a major social problem.

In addition, therapeutic agents for this thrombotic disease have been investigated and developed from all aspects of their pharmacological action.

[Means for Solving the Problems] As a result of extensive research in order to develop a drug useful for the treatment of thrombotic diseases, the present inventors have found that (6)-syogaol has an excellent platelet aggregation inhibiting effect. found that it has
Based on this, the present invention has been completed.

That is, the present invention provides a platelet aggregation inhibitor (hereinafter referred to as a platelet aggregation inhibitor) containing as an active ingredient (6)-shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one] represented by the following formula. , referred to as the drug of the present invention).

(6)-Syogaol, which is the active ingredient of the drug of the present invention, is a main ingredient in the Chinese medicine, Kenbito, etc., which is used in Chinese medicines such as Saiko Keishi Kenbito, Shoseiryuto, and Kakkonto. It is known to have central depressant effects, analgesic effects, etc.

This (6)-syogaol can be obtained, for example, as follows.

The main dried rhizomes are extracted with an extraction solvent such as ether, ethanol, methanol, etc. to obtain an extract, which is then subjected to column chromatography using silica gel as a carrier.
- Develop with an organic solvent such as hexane, acetone, benzene, ethyl acetate, etc. alone or in combination, take a fraction containing (6)-syogaol, and further purify it by preparative thin layer chromatography. This can be obtained by

A specific example is shown below.

[Specific example] Main (Zingiber official Ro
2 kg of dried rhizomes of A. scoe) were ground and extracted under reflux with 3Q ether for 7 hours. The extraction residue was further extracted twice with 3Q ether at reflux for 7 hours. The above extracts were combined and the ether was removed under reduced pressure to obtain an ether extract with an extract weight of 77.059.

Add this ether extract 77.059 to 70% silica gel.
09 (Merck, Kieselgel 60)
The mixture was subjected to column chromatography using a solvent, and developed with a mixed solvent of n-hexane and ether while increasing the proportion of ether.

The fraction eluted with n-hexane:ether (70:30) 0.6Q and 1-hexane:ether ('7
0:30) The fractions eluted in 1.8& were combined, the solvent was removed, and 13. A residue of El was obtained.

This residue was again subjected to column chromatography using silica gel, and n-hexane:ether (95:5)
The eluted fraction was collected and the solvent was removed, resulting in a residue of 5.48 g, which was subjected to preparative thin layer chromatography [plate, Kieselgel 60P F! 54+ developing solvent, n-hexane:acetone (7:3)] to give 0.8039 (yield: 0-.04%) of a pale yellow oily substance. The physical and chemical properties of this pale yellow oily substance are described in the literature (6
) - This is consistent with the physical and chemical properties of shogaol.

Next, the fact that (6)-syogaol, which is the active ingredient of the drug of the present invention, has a platelet aggregation inhibitory effect will be explained using experimental examples.

[Experiment Example 1] ■Preparation of platelet-rich plasma From the femoral artery of a New Norland White male rabbit,
Nine volumes of arterial blood were collected into a polypropylene syringe containing one volume of 3.8% sodium citrate. The collected blood was centrifuged at room temperature for 800 rpm, and the supernatant was collected into platelet-rich plasma (platelet-rich plasma).
plus I! la, PRP). This residue was centrifuged for 3,000 rpm SlS minutes, and the supernatant was collected from platelet-poor-plasma (platelet-poor-plasma).
, P P P ). Using this PPP, P
RP was diluted and the platelet count was adjusted to 3×10′/platelet.

■Measurement of platelet aggregation ability with arachidonic acid After incubating the PRPo, 47 obtained as above for 1 minute at 37°C, constant stirring at 800 rpm was started.
After a minute, 50% of (6)-syogaol obtained in the specific example was added, and after another minute, a 500 μg/mQ arachidonic acid solution was added at 50 degrees to measure the aggregation ability. As a control, physiological saline was used instead of adding (6)=shogaol. Measurement is by PAYTON AGGREGA
TION MODULE (MODEL 600B, PA
The transmittance at the maximum aggregation in the agglutination curve was measured using a nephelometry using YTON ASSOCIATES), and the aggregation inhibition rate was determined when the control was set as 100%. As a result, 50% of (6)-shogaol
The inhibitory concentration (ICs.) was 2.23XIO-8M.

[Experimental Example 2] ■Measurement of aggregation ability by collagen ゛The speed of constant stirring was set to 60 Orpm, and 1 mg/rrtQ collagen solution 507 mm was used instead of the arachidonic acid solution. As a result of measurement in the same manner as above except that J was added, the IC5° of (6)-shogaol was 2.44×10 −5 M.

From these results, it was confirmed that (6)-shogaol, which is the active ingredient of the present invention, has an excellent platelet aggregation inhibiting effect.

Next, an acute toxicity test of (6)-syogaol was conducted using ICR male mice, and LDso was administered intravenously at 50 and 9 mg/kg (up and down).
n method), 687 mg/kg (Litch
field-buying 11 coxon method).

Thus, (6)-syogaol has low toxicity and high safety.

Next, the dosage and formulation of (6)-shogaol obtained in specific examples will be explained.

(6)-Syogaol, which is the active ingredient of the drug of the present invention, can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier. The dosage form is not particularly limited and may be selected and used as appropriate, and includes oral dosage forms such as tablets, capsules, and granules, and parenteral dosage forms such as injections and suppositories.

In order for an oral drug to have the desired effect, it depends on the age, weight, and severity of the disease of the injured person, but it is usually necessary to
) - 20 to 80 B per time including the weight of Shogaol,
It seems appropriate to take it orally up to three times a day.

In the present invention, oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods. Tablets are made by mixing and shaping (6)-syogaol with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc., and capsules are made by mixing and shaping (6)-syogaol. It is made by mixing with an inert pharmaceutical filler or diluent and filling it into hard gelatin capsules, soft gelatin capsules, etc. Syrups and elixirs are produced by mixing (6)-syogaol with sweeteners such as sucrose, preservatives such as methyl and propylparabens, colorants, seasonings, fragrances, and adjuvants.

In order for a parenteral drug to have the desired effect, it usually takes an adult drug (
6) - 0.25 to 10 per day as the weight of shogaol
Intravenous, subcutaneous, or intramuscular injections of up to mg are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and distilled water for injection, physiological saline, aqueous dextrose solution, propylene glycol, etc. can generally be used as a diluent. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into capsules, etc., frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, suppositories for rectal administration, and the like, which are manufactured according to conventional methods.

(6) It has not been reported in the literature that shogaol has a platelet aggregation inhibitory effect, and the drug of the present invention is a drug useful for treating cerebral infarction, cerebral thrombosis, arteriosclerosis, angina pectoris, and the like.

Next, the present invention will be specifically explained with reference to examples, but the present invention is not limited thereto in any way.

Example 1 2.5 g of (6)-syogaol obtained in the specific example was added to 150 g of
- Sterile physiological saline dissolved in polysorbate 80 and heated to 60°C = 1.85f! was added and shaken thoroughly, and the mixture was aseptically dispensed into vials containing 0.5 mg of (6)-syogaol obtained in the specific example, and sealed to produce an injection.

This injection should be shaken before use, and 0.5 g
~207d Administer intravenously.

Example 2 1.5 g of (6)-syogaol obtained in the specific example was mixed with log of silicic acid anhydride, and 85 g of corn starch was added to this.
g and mix further. To this mixture, 50 d of 10% hydroxypropyl cellulose in ethanol solution was added, and the mixture was wetted in a conventional manner, extruded, dried, and sieved to obtain granules of particles of 20 to 50 mesh.

This granule is administered once at ff10.7 to 2.
6g (7-27m as the weight of (6)-shogaol)
(equivalent to g) three times a day.

Example 3 (6)-Shyogaol 7, Og obtained in the specific example was mixed with 20 g of silicic anhydride, and microcrystalline cellulose log,
Magnesium stearate 3.0g.

65 g of lactose was added and mixed, and this mixture was compressed using a single-shot tablet machine to produce tablets with a diameter of 7IIIN and an amount of 100 mg.

One tablet of the present invention contains 6.7 mg of (6)-shogaol. This tablet is taken 1 to 4 tablets at a time, three times a day.

Example 4 1 g of (6)-syogaol 6゜7Il obtained in the specific example was mixed with 200 mg of silicic anhydride, and lactose 80i+ was added to this.
g was added thereto, mixed, and filled into No. 0 gelatin capsules to obtain capsules.

This capsule preparation is taken at a time of 1 to 4 capsules up to 3 times a day, depending on the symptoms.

Claims (1)

[Claims] (6) - Platelet aggregation inhibitor containing shogaol as an active ingredient.