JPH0228567B2 - KATSUKASHOCHIRYOZAI - Google Patents

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides (6)-syogaol [(6)-
The present invention relates to a therapeutic agent for keratosis containing ``shogaol'' as an active ingredient.

[Prior Art and Problems] Keratosis represented by psoriasis has been on the rise in recent years, and in psoriasis in particular, the main morphological change in the affected skin is due to markedly accelerated turnover of epidermal cells. These include thickening of the epidermal cell layer and abnormal keratosis, as well as inflammatory reactions in the papillary epidermal layer and migration of polynuclear leukocytes into the epidermal cell layer.

Until now, steroids have been used as therapeutic agents for this keratosis, but serious side effects have become a problem. Further, the use of vitamin A derivatives (retinoids) is restricted due to the problem of teratogenicity, and to date, there has been no innovative therapeutic agent for this keratosis.

[Means for Solving the Problems] As a result of intensive study to develop a drug effective for this keratosis, the present inventors have found that (6)-Syogaol has an excellent effect on the treatment of keratosis. Based on this finding, the present invention has been completed.

That is, the present invention provides the following formula A therapeutic agent for keratosis containing (6)-syogaol [1-(4-hydroxy-3-methoxyphenyl)-(E)-4-decen-3-one] as an active ingredient (hereinafter referred to as "this book"). (referred to as the drug of invention).

(6)-shogaol, which is the active ingredient of the drug of the present invention, is used, for example, in the Chinese herbal medicine saikokeishikankyoto,
It is a component contained in Chinese medicine, dried ginger, or ginger, which is used in products such as Shoseiryuto and Kakkonto, and is known to have central depressant and analgesic effects.

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

The dried rhizomes of the ginger are extracted with organic solvents such as ether, ethanol, methanol, etc. to obtain an extract, which is then subjected to column chromatography using silica gel as a carrier. The fraction containing (6)-syogaol is obtained by developing with organic solvents alone or in combination, and this can be further purified by preparative thin layer chromatography.

A specific example of the production of (6)-shogaol is shown below.

[Specific Example] 2 kg of dried rhizomes of Zingiber officinale Roscoe were ground and extracted under reflux with ether 3 for 7 hours. The extraction residue was further treated with ether 3 twice.
Extraction was carried out under reflux for 7 hours. The above extracts were combined and the ether was removed under reduced pressure to obtain 77.05 g of extracted extract.

Add 77.05g of this ether extract to silica gel.
The mixture was subjected to column chromatography using 700 g (Merck, Kieselgel 60) 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) 0.6 and the fraction eluted with n-hexane:ether (60:40) 1.6 were combined and the solvent was removed to obtain 13.6 g of residue. This residue was again subjected to column chromatography using silica gel, and n-hexane:ether (95:
5) The fraction eluted in step 5) was fractionated, and the resulting residue (5.48 g) was subjected to preparative thin layer chromatography [plate, kieselgel60PF ₂₅₄ : developing solvent, n
-hexane:acetone (7:3)] to obtain 803 mg (yield 0.04%) of a pale yellow oily substance. The physicochemical properties of this pale yellow oily substance were consistent with those of (6)-syogaol described in the literature.

Next, the fact that (6)-shogaol, which is the active ingredient of the drug of the present invention, has a therapeutic effect on keratosis will be explained using experimental examples.

[Experiment example] Growth inhibitory effect on epidermal growth factor (EGF) Fibroblasts (BALB/C 3T3) were placed in a 24-well plate.
cells) were prepared to contain 2.5× ¹⁰⁴ cells in 0.5ml.
Culture medium containing 10% calf serum (CS DMEM)
) was injected at a rate of 0.5 ml per hole. After the fibroblasts were saturated in a monolayer, 1%
Instead of CS DMEM, culture at 37°C and 5% _CO2 for 12 hours, and (6)-Syogaol, EGF (Collaborative
research, lnc.) was added and cultured for an additional 16 hours. Add to this 0.5μCi/50μ/
After adding ³ H-thymidine to the well and culturing for 8 hours, the culture medium was removed, washed with cooled saline-containing phosphate buffer, and 5% cold trichloroacetic acid was added.
It was left for 30 minutes. After removing the supernatant, dissolve in 0.5M aqueous sodium hydroxide solution, neutralize with 0.5M hydrochloric acid,
Counts were performed using a liquid scintillation counter. ^3H taken into cells as a result of this proliferation
- Measuring the radioactivity of thymidine on cell proliferation
(6) - The effects of shogaol were investigated. As a result, the proliferation of balb/c was promoted by EGF.
A 52.7% growth inhibition was observed for 3T3 cells.

From this result, it was confirmed that (6)-shogaol has an excellent keratosis treatment effect.

Next, we conducted an acute toxicity test of (6)-shogaol.
When conducted using ICR male mice, LD ₅₀
is 50.9mg/Kg (up and down method) by intravenous administration,
687mg/Kg by oral administration (Litchfield-Wilcoxon method)
It was hot.

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

Next, the dosage and formulation of (6)-shogaol, which is the active ingredient of the drug of the present invention, will be explained.

The compounds of this invention can be administered to animals and humans either neat or with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as necessary, including tablets, capsules,
Examples include oral preparations such as granules, fine granules, and powders, and parenteral preparations such as injections and suppositories.

In order to exert the desired effect as an oral agent,
Although it varies depending on the patient's age, weight, and severity of the disease,
Normally for an adult (6) - 20 ~ as the weight of shogaol
It seems appropriate to take 80mg in divided doses several times a day.

In the present invention, oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, cornstarch, inorganic salts, and the like.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, 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 80.

[Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate,
Polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The drug of the present invention can also be administered as a suspension, emulsion, syrup, or elixir, and these various dosage forms may contain flavoring agents and coloring agents.

In order to exert the desired effect as a parenteral agent, it is usually necessary for adults to administer 0.25 to 10 mg of (6)-Syogaol intravenously per day, although this will vary depending on the age, weight, and severity of the disease of the patient. Intravenous drip, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and diluents generally include distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, mustard oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. can be used. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the standpoint of stability, this parenteral preparation is frozen after being filled into vials, etc.
The liquid formulation can also be reconstituted from the lyophilizate immediately prior to use by removing moisture by conventional lyophilization techniques. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

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

The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

Example 1 Cornstarch 23.5g Crystalline cellulose 15g Carboxymethylcellulose calcium 5g Light anhydrous silicic acid 0.5g Magnesium stearate 1g (6)-Syogaol 5g Total 50g Mix ~ uniformly according to the above recipe and compress with a tablet machine It was molded to obtain 200 mg tablets.

One tablet of this tablet contains 20 mg of (6)-shogaol, and adults should take 1 to 4 tablets a day in several doses.

Example 2 Crystalline cellulose 39.5g Magnesium stearate 0.5g Carboxymethyl cellulose calcium 5g (6)-Shyogaol 5g Total 50g According to the above recipe, parts of ~ and were mixed uniformly, compressed, and then crushed, and The remaining amount was added to the mixture, mixed, and compressed using a tablet machine to obtain tablets each weighing 200 mg.

One tablet of this tablet contains 20 mg of (6)-shogaol, and adults should take 1 to 4 tablets a day in several doses.

Example 3 Crystalline cellulose 17g 10% hydroxypropylcellulose ethanol solution 25g Carboxymethylcellulose calcium
2.7g Magnesium stearate 0.3g (6) - Shogaol 5g Total 50g According to the above recipe, and are mixed uniformly, netted by a conventional method, granulated using an extrusion granulator, dried and crushed. After that, and were mixed and compressed using a tablet machine to obtain tablets each weighing 200 mg.

One tablet of this tablet contains 20 mg of (6)-shogaol, and adults should take 1 to 4 tablets a day in several doses.

Example 4 Corn starch 43g Magnesium stearate 0.5g Calcium carboxymethylcellulose 5g Light anhydrous silicic acid 0.5g (6)-Syogaol 1g Total 50g Mix ~ uniformly according to the above recipe, and after compression molding with a compression molding machine, Shredded by a crusher,
Granules were obtained by sieving.

1g of this granule contains 20mg of (6)-syogaol.
It contains 1 to 4 g per day for adults, divided into several doses.

Example 5 Crystalline cellulose 29g 10% hydroxypropyl cellulose ethanol solution 20g (6)-Shyogaol 1g Total 50g According to the above recipe, ~ were mixed uniformly and were made into a suspension. After granulation using an extrusion granulator, the mixture was dried and sieved to obtain granules.

1g of this granule contains 20mg of (6)-syogaol.
It contains 1 to 4 g per day for adults, divided into several doses.

Example 6 Cornstarch 44.5g Light anhydrous silicic acid 0.5g (6)-Shyogaol 5g Total 50g Mix ~ uniformly according to the above recipe,
200 mg was filled into No. 2 capsules.

One capsule of this preparation contains 20 mg of (6)-shogaol, and adults should take 1 to 4 capsules a day in divided doses.

Example 7 Distilled water for injection Appropriate amount Glucose 200 mg (6)-Shyogaol 1 mg total amount 5 ml After dissolving and in distilled water for injection,
The mixture was injected into a ml ampoule and autoclaved at 121°C for 15 minutes to obtain an injection.

Example 8 (6)-Syogaol 0.05g White petrolatum 25g Stearyl alcohol 22g White beeswax 15g Polyoxyethylene (25) monostearate 2.3g Sorbitan monopalmitate 2.7g Propyl paraoxybenzoate 0.05g Methyl paraoxybenzoate 0.05g Purification Water 32.85g Total 100g According to the above recipe, - were mixed uniformly and heated to dissolve to obtain an ointment.

Claims (1)

[Claims] 1 (6) - A therapeutic agent for keratosis containing shogaol as an active ingredient.