JPH0794388B2 - Remedy for psoriasis - Google Patents

Description

TECHNICAL FIELD The present invention relates to a therapeutic agent for psoriasis containing a sembrane-type diterpene compound as an active ingredient.

(Prior Art) Sembrane-type diterpene compounds are
a) and coelenterates belonging to the order Alcyonacea, and has recently been found to have cavitary tumor activity and has attracted attention. [For example, B.Turs
ch) et al., Tetrahedron, Vol. 31, 129.
Page, 1975, UK and Weinheimer (AJWe
inheimer) et al., Tetrahedro
In view of such circumstances, Hirayama et al. have focused their attention on the coelenterate worm (Sarcophyton glaucum), which belongs to the order Lepidoptera, and found that it has an anti-solid tumor action. We have found a new semblanc type diterpene compound. [See, for example, JP-A-56-61318] However, it has only been reported so far that the compound has an anti-solid tumor action, and there has been no report on the action on psoriasis.

Psoriasis is a skin disease in which the number of patients is gradually increasing in recent years, and its symptoms include erythema of half-rice size on the skin.
After that, when silver-white scales are fixed and peeled off with force, punctate hemorrhages (Auspices phenomenon) are observed on the bright red erythema surface. Small spotted erythema and papules accompanied by spotted scales, and these individual eruptions expand in a centrifugal form to a copper coin size, but sometimes they fuse and become a palm size to form an irregular map. There are no subjective or systemic symptoms, but the symptoms become chronic and remission and aggravation repeat.

This cause is thought to be based on genetic factors, but there are various theories that it is due to the addition of abnormal lipid metabolism to the local hypermetabolism predisposition or one of autoimmune diseases. Not confirmed. In any case, abnormal growth of epidermal basal layer cells was observed, and due to this abnormal growth,
Normally, it takes about 28 days for basal cells to divide, keratinize, and desquamate, but this period is significantly shortened, and as a result, the above-mentioned auspices phenomenon occurs. Therefore, for the treatment of psoriasis, it is important to suppress the abnormal proliferation of basal cells and suppress the thickening of the skin.

As a conventional treatment method, a method using a corticosteroid, Geckelman's therapy, etc. are known, and in recent years, retinoid compounds have been developed as a therapeutic agent for psoriasis.

Corticosteroids may show a marked effect, but they are difficult to use for a long period of time due to their unique side effects known as enthusiosis.

Also, Geckelmann therapy applies coal tar to the affected area,
The next day, it is lightly removed with a spatula and wiped with olive oil, then the same area is irradiated with ultraviolet rays, and a bath is used to remove scales with a soap and a brush. This is a therapy that puts a considerable burden on the patient in that it takes time and labor and causes discomfort in appearance.

Since retinoid compounds have side effects of vitamin A and are accompanied by symptoms such as hair loss, skin atrophy, skeletal disorders, and bleeding, their use is limited.

(Problems to be Solved by the Invention) The present inventors proceed with the research for the purpose of suppressing the abnormal proliferation of epidermal basal layer cells, suppressing the thickening of the cover sheet, and developing an effective component having a therapeutic effect on psoriasis. During the process, we focused our attention on the effect on the skin of the sembrane-type diterpene compound contained in the coelenterate C. elegans, and as a result of extensive studies, the compound strongly suppressed the abnormal proliferation of epithelial basal layer cells. The inventors have found that they have an action and completed the present invention.

(Means for Solving Problems and Actions Thereof) That is, the present invention provides the following general formula (I): (In the formula, R represents a hydrogen atom or an acyl group.) A therapeutic agent for psoriasis containing a sembrane-type diterpene compound represented by the formula.

Hereinafter, the present invention will be described in detail.

The cembrane-type diterpene compound represented by the above general formula (I) used in the present invention is obtained from a coelenterate animal, Sarcophyton glaucum, belonging to the order Umitosaka, by a method described in, for example, JP-A-56-61318. can get.

That is, the compound according to the present invention can be separated by silica gel column chromatography from the lipid fraction of the extract of C. communis.

It is known that the holly mushrooms usually inhabit the coral reefs of the Indian Ocean and the Pacific Ocean, for example, the holly mushrooms that inhabit the Red Sea include sarcophine and 16-deoxosarcophine. [Bernstein (J.Be
rnstein) et al., Tetrahedron, Vol. 30, 2817, 1974,
See England and Y. Kashman et al., Tetrahedron, Vol. 30, page 3615, 1974, United Kingdom.] The components contained in the holly mushroom may differ depending on the time and place of collection. Need to decide.

During extraction, it is preferable to dehydrate and shred so that the surface becomes less viscous.

Extraction solvents include, for example, alcohols such as methanol, ethanol, isopropanol; halogenated hydrocarbons such as chloroform; hydrocarbons such as benzene, hexane, heptane; ethers such as ethyl ether, isopropyl ether, dioxane; acetone, methyl ethyl ketone. And the like; organic solvents such as esters such as ethyl acetate, and mixed solvents thereof.

During the extraction operation, in order to avoid decomposition of the contained components, it is preferable to make the contact area with the air as small as possible or to make it under an inert gas atmosphere. The extraction can be carried out at room temperature, but in order to accelerate the extraction, it may be carried out under heating.

The solvent of the extract obtained by separating from the residue by a conventional method can be distilled off by a conventional method to obtain a crude extract.

The crude extract may be treated with activated carbon or a conventional method (for example, Forsch (J.
Folch) -Forsch et al., Journal of Biological Chemistry (J. Biol. Chem) vol. 226, 49.
Page 7, 1957, refer to the United States]].

The lipid fraction of the extract of C. mellifera thus obtained is a viscous brown oil.

Further purification may be done by chromatography.
Chromatography may be either column chromatography or preparative thin layer chromatography.

As a packing material for column chromatography, silica gel, alumina, cellulose powder, activated carbon or the like is used. The elution solvent may be appropriately selected and determined according to the filler, but when silica gel is used as the filler, hexane, hexane-ethyl acetate (volume ratio 0.95 to 0.
9: 0.05-0.1) and the like are preferable. The crude fraction obtained here can be further purified and isolated by column chromatography by changing the packing material and the elution solvent.

As the gel for preparative thin layer chromatography, silica gel, alumina, cellulose powder or the like is used.
As the developing solvent, a hexane-acetic acid ethyl ester mixed solvent is suitable.

Among the compounds represented by the general formula (I) thus obtained, those in which R is a hydrogen atom are named as Sarcophytol-A.

When this sarcophytol-A is acylated by a conventional method, an acylated product such as sarcophytol-A acetate is obtained, and when this sarcophytol-A acylated product is esterified by a conventional method, sarcophytol-A is obtained.

As the active ingredient of the present invention, it is not always necessary to use a pure product of the sembrane-type diralpene compound represented by the general formula (I) thus isolated, and a mixture of these substances or an extract containing the same. A partially purified product or the like can also be used.

The cembran-type diterpene compound obtained by the above-mentioned method or an extract or partially purified product of C. mellifera containing the compound is added to the drug of the present invention as an active ingredient.

The therapeutic agent for psoriasis according to the present invention can be administered by any method, but the following method is preferably carried out.

That is, parenteral administration such as application to the affected area, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection and the like, and oral administration are also possible.

The dose is determined according to the patient's age, health condition, weight, type of treatment if there is simultaneous treatment, treatment frequency, desired effect properties, etc. In general, the daily dose of the active ingredient is 0.0001.
˜2,000 mg, particularly 0.1 to 500 mg is preferable, and it is administered once or dividedly (preferably by application to the affected area or oral administration).

For oral administration, tablets, capsules, powders, elixirs, etc. are used.For parenteral administration, the affected area is applied in a sterilized form such as ointment, liquid or suspension, and subcutaneous injection. Intravenous injection, intramuscular injection, intraperitoneal injection and the like are used in a sterilized liquid form such as liquid or suspension. When used in the form as described above, a solid or liquid non-toxic pharmaceutical carrier may be included in the composition.

As an example of the solid carrier, a usual gelatin type capsule is used. In addition, the active ingredient is tableted or powdered with or without an auxiliary drug.

These capsules, tablets and powders generally contain from 5 to 95% by weight of active ingredient, preferably from 25 to 90%.

As an ointment carrier, beeswax, liquid paraffin, a base such as stearic acid and water or a mixture thereof may be blended, and if necessary, a surfactant such as sorbitan monofatty acid ester or an emulsifier such as KOH, glycerin, etc. Moisturizers, emulsifying agents such as cetanol, lower alcohols such as ethanol, thickeners, fragrances, antioxidants, chelating agents, dyes, antiseptic and antifungal agents, and other conventional ingredients used in ointments can be blended. The blending amount may be in the range usually used. In the case of these ointments, it is usually mixed in the range of 0.00001 to 10% by weight.

As the liquid carrier, acetone, lower alcohol, peanut oil, soybean oil, mineral oil, rubber oil or other animal or plant origin,
Alternatively, synthetic oil or the like is used. Saline,
Dextrose or similar sugar solutions, glycols such as ethylene glycol, propylene glycol, polyethylene glycol are preferred as liquid carriers.

When administered parenterally by intramuscular injection, intravenous injection or subcutaneous injection, it is used as a sterile solution to which other solutes such as salt or glucose are added in order to make the solution isotonic.

Suitable solvents for injection include sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, liquid for intravenous injection, electrolyte solution (for intravenous injection) and the like. In the case of these injections, usually 0.5 to 20% by weight,
It is preferable to contain 1 to 10% by weight of the active ingredient.

For oral administration, suspensions or syrups containing 0.5-10% by weight of active ingredient are preferred. In this case, a carrier such as a flavoring agent, a syrup, an aqueous excipient such as a pharmaceutical micelle is used.

(Effect of the Invention) The therapeutic agent for psoriasis of the present invention acts on epithelial basal layer cells, suppresses abnormal growth thereof, suppresses epidermal thickening, and consequently reduces psoriasis symptoms and eliminates skin rashes.

(Example) Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless the gist thereof is exceeded.

Example 1 Hair of the back of CD-1 male mice (15 to 25 g) is shaved and further treated with a depilatory cream to maintain the depilatory state for about 1 to 2 weeks. (The area is about 3 to 5 cm ² ) When 2.5 μg of teleocidin was dissolved in 0.1 ml of acetone and applied to the hair loss part of the mouse in this state, the skin of the part thickened after 3 days and the normal epithelium thickness was reduced. The thickness is about 0.2 mm while it is about 0.05 mm. Using 6 such models, 1.6 μg of sarcophytol A dissolved in 0.1 ml of acetone was applied in advance, and 10 minutes after that, 2.5 μg of teleocidin dissolved in 0.1 ml of acetone was applied. After 3 days, the skin of these mice was collected and the thickness of the epithelium was measured.

The result was calculated as an average value of 6 mice and is shown in Table 1.

The epithelium thickness was measured and averaged in the same manner as above, using a control group to which 0.1 ml of acetone had been applied 10 minutes before the application of teleocidin. The results are shown in Table 1.

Claims (1)

[Claims] 1. The following general formula (I): (In the formula, R represents a hydrogen atom or an acyl group.) A therapeutic agent for psoriasis containing a sembrane-type diterpene compound represented by the formula.