JPH07300421A - Anti-inflammatory agent - Google Patents

Abstract

PURPOSE:To obtain an anti-inflammatory agent having stability of an active ingredient higher than that of a conventional anti-inflammatory agent blended with astaxanthin, being expected to have higher effect, capable of lightening adverse effect of other anti-inflammatory agents and medicine components. CONSTITUTION:An anti-inflammatory agent comprises a diester of astaxanthin, preferably a fatty acid diester or a glycerophosphoric acid diester of astaxanthin. The diesters are extracted from a krill. When the diesters are identified by using a high-performance liquid chromatography, a column of RPC Microbondapach NH2 made of Waters Inc. (deltamm. i. dX-10mm) is used and n-hexane:2-propanolmethanol=75:15 is used for a mobile phase. In the case of making the diester flow at 2m/minute flow rate and observing absorption at 470nm by an ultraviolet light and visible light absorption spectrum detector, the diesters having a retention time providing the maximum peak in the range of 0.5-2.5 minute are preferable. When the diesters are blended with an aspirin preparation, adverse effects are lightened and an aspirin acid agent having increased effect can be obtained.

Description

Detailed Description of the Invention

[001]

TECHNICAL FIELD The present invention relates to an anti-inflammatory agent containing a special astaxanthin derivative.

[002]

It has been already known to use astaxanthin alone or a partial ester derivative of astaxanthin as an anti-inflammatory agent. For example, Japanese Patent Laid-Open No. 2-4
In 9091, astaxanthin, astaxanthin oleate, palmitate, stearate and other astaxanthin monoesters are used as active ingredients of anti-inflammatory agents.

However, these simple substances of astaxanthin and monoesters of astaxanthin are easily susceptible to oxidative decomposition by oxygen in the air and have poor physical stability, and are decomposed with time during the manufacturing process of the anti-inflammatory agent and the storage period of the preparation. Deactivates effectiveness.

Further, the simple substance or monoester of astaxanthin has a drawback that it is difficult to be absorbed into the living body through the intestinal tract or the skin.

Further, the known monoester of astaxanthin has a drawback that it is expensive and difficult to use as a general-purpose anti-inflammatory agent.

On the other hand, many medicines are currently restricted from being used smoothly due to their side effect problems, but in order to reduce the side effects of medicines, there is only effective means for developing new drugs without side effects. There was a problem that enormous development cost and time were required.

Aspirin is one of the most widely used ingredients as an anti-inflammatory agent at present, but when a formulation containing aspirin is taken, anorexia, heartburn, stomachache, nausea, vomiting, gastrointestinal bleeding, tinnitus, Hearing loss, dizziness, headache,
There is a problem that it is difficult to use because it may cause side effects such as agitation, hyperventilation, metabolic acidosis, rash, edema, rhinitis-like symptoms, conjunctivitis, exfoliative dermatitis, brain disease, and Reye's syndrome.

[0085]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention An object of the present invention is to provide an anti-inflammatory agent containing astaxanthin diester as a main component, which is physically stable, easily absorbed from the intestinal tract and skin, and available at low cost. . And a astaxanthin diester compound, which provides a pharmaceutical with reduced side effects and an aspirin preparation.

[0109]

In view of such circumstances, the present inventors have been keen to develop an astaxanthin derivative that is stable in the manufacturing process and over time, is easily absorbed from the intestinal tract and skin, and is available at low cost. As a result of repeated studies, it was found that the diester derivatives of astaxanthin satisfy these conditions and show an excellent effect as an active ingredient of an anti-inflammatory agent, and these diesters are a drug in which side effects such as aspirin preparations are a problem. It was found that the side effects of the drug can be reduced by adding it to the class. Further, it was found that these effects are particularly effective for astaxanthin diester separated under specific HPLC conditions and astaxanthin diester extracted from krill, and the present invention has been completed. That is, the present invention provides an anti-inflammatory agent characterized by containing asesters of diesters of asquxanthin and a drug with reduced side effects. Hereinafter, the present invention will be described in more detail.

Astaxanthin constituting the astaxanthin diester of the present invention is 3,3′-dihydroxy-
It is β, β-carotene-4,4′-dione or a stereoisomer thereof.

The stereoisomer of this astaxanthin is (3
R, 3'R) -astaxanthin, (3R, 3'S)-
There are astaxanthin and (3S, 3 ′S) -astaxanthin, but any stereoisomer thereof can be used in the present invention.

The astaxanthin diesters according to claims 1 to 7 of the present invention are not particularly limited as long as they are substances capable of having a diester structure, and specific examples thereof include those having the following structural formulas.

[0113]

A and B are —OR (R is a hydrocarbon having 1 to 50 carbon atoms), amino acid esters such as glycine and alanine, carboxylic acid esters such as acetic acid ester and citric acid ester and salts thereof, or Inorganic acid esters and salts thereof such as phosphoric acid ester and sulfuric acid ester, sugar ester (glycoside) such as glucoside, or fatty acid ester selected from highly unsaturated fatty acid, unsaturated fatty acid or saturated fatty acid, sugar fatty acid It is composed of the same or different diesters selected from esters, glycerosugar fatty acid esters, sphingosugar fatty acid esters, glycerofatty acid esters, glycerophosphoric acid esters and the like.

The astaxanthin glycerophosphate diester of the present invention has the following structural formula.

[0163]

(A and B are selected from fatty acid esters such as oleic acid ester, palmitic acid ester, and stearic acid ester, or glycerophosphoric acid esters having the following structural formula.)

The

(R is hydrogen or a highly unsaturated fatty acid such as DHA, EPA, linoleic acid, linolenic acid or arachidonic acid,
It is selected from fatty acids selected from unsaturated fatty acids or saturated fatty acids. X is selected from hydrogen or choline, ethanolamine, serine, inositol. )

Of these astaxanthin diesters, astaxanthin diesters which are particularly suitable as a raw material for an anti-inflammatory agent which has good stability, is inexpensive, and is relatively easily available, include astaxanthin fatty acid esters. There are glycerophosphoric acid diesters of the class and astaxanthin.

Examples of astaxanthin fatty acid diesters which are particularly effective as anti-inflammatory agents include astaxanthin dilaurate, astaxanthin dimyristate, astaxanthin dipentadecanoate, astaxanthin dipalmitate, astaxanthin dipalmitoolein. Acid ester,
Astaxanthin diheptadecanoic acid ester, astaxanthin dielaidic acid ester, astaxanthin diricinoleic acid ester, astaxanthin petroselinic acid ester, astaxanthin vaccenic acid ester, astaxanthin eleostearic acid ester, astaxanthin punisinic acid ester, astaxanthin licanoic acid ester, astaxanthin paris Naline ester,
Astaxanthin gadolate, astaxanthin 5-eicosenoate, astaxanthin 5-docosenate, astaxanthin cetoleate, astaxanthin erucate, astaxanthin 5,13-docosadienoate, astaxanthin cerakolate, astaxanthin decenoate, Astaxanthin steric acid ester,
Astaxanthin fatty acid such as astaxanthin dodecenoic acid ester, astaxanthin dioleic acid ester, astaxanthin distearic acid ester, astaxanthin dieicosapentaenoic acid ester, astaxanthin didocosahexaenoic acid ester, astaxanthin dilinoleic acid ester, astaxanthin dilinolenic acid ester, astaxanthin diarachidonic acid ester There are esters.

Examples of astaxanthin diglycerophosphates include astaxanthin diglycerophosphate, astaxanthin glycerophosphate palmitic acid,
Astaxanthin glycerophosphatidyl choline palmitate, Astaxanthin glycero phosphatidyl choline DHA, Astaxanthin glycero phosphatidyl inositol palmitate, Astaxanthin glycero phosphatidyl inositol DHA, Astaxanthin glycero phosphatidyl inositol linoleic acid, astaxanthin glycerophosphoryl Acid etc.

As the astaxanthin diester of the present invention, a natural astaxanthin diester-containing substance of biological origin having astaxanthin can also be used. Examples of these naturally-derived astaxanthin diester-containing products include yeasts such as Phaffia, algae such as Haematococcus, seed plants such as Fusozo, and jejunal animals such as coral, krill, shrimp, and crustaceans such as crabs. Astaxanthin diesters derived from krill, which are inexpensive and have a low odor and excellent pharmacological activity, are particularly useful.

The krill according to claim 2 of the present invention may be any crustacea of the order Krill belonging to the subgenus Coleoptera or an extract thereof. Examples of krill are commonly known as krill, Antarctic krill, or Krill, Eufacia cea superba (or Eufacia superba).
And Eufacia sea nitricifanes, Eufacia sea nematosus cellis, and Eufacia sea pacifica. Among them, Antarctic krill is particularly suitable as a krill to be used in the present invention because it can be captured in large quantities at low cost.

As the astaxanthin diester according to claim 2 of the present invention, an extract such as a frozen product, a cooked product, a steamed product, a dried product or a crushed product of krill can be used.

The extraction method, concentration method, purification method, etc. of the krill diester-type astaxanthin according to claim 2 of the present invention are described in JP-A-3-48884 and JP-A-2-49091, and the natural carotenoids such as free astaxanthin. It is also possible to use the above-mentioned extraction method, or the conventional extraction method of oil-soluble components from natural products.

For example, since the diester-type astaxanthin is an oil-soluble substance, if necessary, those natural products are extracted with an oil-soluble organic solvent such as acetone, alcohol, ethyl acetate, benzene or chloroform to extract the astaxanthin-containing component, which is harmful. The organic solvent is removed by a conventional method to obtain a diester-type astaxanthin concentrate, but the extraction method is not particularly limited. It is also possible to emulsify these with the existing emulsifiers described in the 12th Amended Japanese Pharmacy Law (Hirokawa Shoten, 1991) and the 6th edition Official Guidebook for Food Additives (Hirokawa Shoten, 1992).

According to the studies conducted by the present inventors, if the astaxanthin diester content in the total astaxanthin in these natural extracts is low, the sufficient stability and anti-inflammatory effect aimed at by the present invention cannot be exerted. According to the study of the present inventor, when measured by a high performance liquid chromatogram (HPLC) method under the following conditions, the natural extract that can be used in the present invention has a peak area ratio of astaxanthin diester of 30% or more of the total astaxanthin. Must be an extract.

Specifically, a column of Waters Microphone Pack NH ₂ (8 mm.i.d.times.100 mm) was used, n-hexane: 2-propanol: methanol = 75: 15: 15 was used as a mobile phase, and a flow rate was 2 ml. / M
in. When the mobile phase is flowed in, the absorption time at 470 nm is observed by the UV-visible absorption spectrum detector, the retention time is 0.
When the ratio of the peak area of the diester of astaxanthin with respect to the sum of the peak areas of astaxanthin and its derivatives of from 5 minutes to 5 minutes is calculated as 100%, it is an extract containing 30% or more of the total astaxanthin peak area. There must be.

According to the studies conducted by the present inventors, the astaxanthin diesters having a maximum peak at a retention time of 0.5 minutes to 2 minutes and 30 seconds under the same HPLC conditions as described above were astaxanthin simple substance and a monoester derivative of astaxanthin. It is an excellent raw material for anti-inflammatory agents and side-effect reducing agents for aspirin, because it is inexpensive and can be obtained in large quantities and has high stability.

As the astaxanthin diester of the present invention, there may be a case where a commercially available astaxanthin diester-containing extract satisfying the above-mentioned HPLC conditions can be used. Examples thereof include Astax (Atax) manufactured by Itano Refrigeration Co., and krill oil. But is not limited to this.

The following drugs and their side effects are given as examples of the drugs having side effects, and the side effects thereof, in which the astaxanthin diester according to claim 6 of the present invention can exert a side effect reducing effect.

Teratogenic and gastrointestinal disorders that are a side effect of steroidal anti-inflammatory drugs such as hydrocortisone. Gastrointestinal disorders that are a side effect of non-steroidal anti-inflammatory drugs such as aspirin, phenylbutazone, indomethacin, mefenamic acid, ibuprofen. Neurological disorders and blood disorders that are side effects of anti-AIDS drugs such as AZT. Myelopathies and teratogenesis, which are side effects of antineoplastic drugs such as nitrogen mustard. Bone marrow disorder, teratogenesis, liver disorder, and neuropathic disorder which are side effects of antibiotics such as chloramphenicol, tetracycline, streptomycin, kanamycin. There are neurological disorders and blood disorders which are side effects of antipsychotic drugs such as chlorpromazine and reserpine.

The amount of the astaxanthin diester compounded in the anti-inflammatory agent of the present invention in the anti-inflammatory agent varies depending on the degree of purification and purity of the astaxanthin diester, but these astaxanthin derivatives in the anti-inflammatory agent are converted to pure products. Therefore, it may be added in an amount of 0.001% by weight or more.

The astaxanthin diester is compounded in a drug having side effects and an aspirin preparation in such a proportion that 0.01 mol or more of astaxanthin diester is added to 1 mol of a drug having side effects. For example, in the case of aspirin, aspirin aluminum 1mo
The drug may be formulated by adding 0.01 mol or more of astaxanthin diester to 1 in terms of pure product.

The dosage form of the anti-inflammatory agent of the present invention includes toothpaste, mouthwash, oral agents such as troches, bath agents, shampoo, rinse, hair tonic, hair cream, hair nourishing agent, hair restorer, scalp agent and the like. Cosmetics such as scalp hair preparations, creams, lotions, milky lotions, lip balms, and packs, pharmaceuticals such as tablets, capsules, soft capsules, health foods, and anti- eye drops, ointments, coatings, poultices, etc. All dosage forms to which flame ingredients can be added can be taken.

When the anti-inflammatory agent of the present invention is used in combination with or mixed with an existing anti-inflammatory component or anti-inflammatory component, a synergistic effect of anti-inflammatory action can be exerted. Therefore, these existing anti-inflammatory components or anti-inflammatory components are used in combination with or mixed with a diester of astaxanthin. can do. It is considered that this is because the anti-inflammatory action of the existing anti-inflammatory drug and the astaxanthin diester act by different physiological mechanisms.

As the antiphlogistic component capable of exhibiting these synergistic effects, aniline derivative type antiphlogistic agent, salicylic acid derivative type antiphlogistic agent, pyrazolone derivative type antiphlogistic agent, indomethacin type antiphlogistic agent, mefenamic acid type antiphlogistic agent, antigout agent, anticonvulsant Drugs, antitussives, expectorants, bronchodilators, respiratory function improving agents, antihistamines, antiallergic agents, and inflammatory enzyme agents.

To the anti-inflammatory agent containing the astaxanthin diester of the present invention, a substance having an antioxidant ability can be added as a stabilizer. For example, vitamin A vitamin B,
Vitamin C, vitamin E and their vitamin derivatives,
Astaxanthin simple substance, astaxanthin monoester, cysteine, glutathione, glutathione peroxidase, citrates, phosphates, polyphenols,
One or a mixture of two or more selected from nucleic acids, Chinese herbs, seaweeds, inorganic substances, and existing antioxidants described in the Japanese Pharmacopoeia as having an antioxidant function can also be added in combination.

As the astaxanthin diester compound and the monoxerophosphoric acid derivative of astaxanthin to be incorporated in the anti-inflammatory agent of the present invention, a protein conjugate of the astaxanthin diester derivative and the astaxanthin monoguscerophosphate derivative can also be used.

The protein conjugate of astaxanthin diester to be incorporated in the anti-inflammatory agent of the present invention is not particularly limited as long as these derivatives are bound to the protein.

The astaxanthin-protein conjugate of the present invention may be any one in which astaxanthin and a protein are bound, and examples thereof include, but are not limited to, actomyosin-binding astaxanthin.

The astaxanthin diesters of the present invention are superior in physical stability to the astaxanthin monoesters. It is considered that this is because both of the two OH groups of astaxanthin are protected against air oxidation by the ester bond, but in the living body, the ester bond is hydrolyzed by the enzyme and converted into the free astaxanthin form. Therefore, it has no effect on the pharmacological effect of astaxanthin.

Astaxanthin simple substance and astaxanthin monoester are rapidly decomposed during the manufacturing process and storage period of the anti-inflammatory agent to rapidly eliminate the pharmacological action of astaxanthin, but the astaxanthin diester form is more than the free form. Much better stability.

If necessary, the astaxanthin diester of the present invention may be coated with a coating agent such as gelatin, oils and fats.

[046]

The astaxanthin diesters added to the anti-inflammatory agent of the present invention are physically more stable than astaxanthin and the monoester of astaxanthin because the two hydroxyl groups of astaxanthin are protected by ester bonds, and are oxidized in the preparation. Hard to disassemble. However, when it is taken up in the living body, it is rapidly hydrolyzed to astaxanthin by the enzyme in the living body, and due to the presence of two keto groups and water-dispersing groups in the molecule, it shows extremely high radical scavenging action in living tissues and produces lipid hydroperoxide. By suppressing and preventing the production of lipid peroxide, it is considered to stably exhibit an excellent action for recovery, delay, prevention of inflammation of living cells and reduction of side effects of drugs.

[047]

EXAMPLES The present invention will now be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Example 1 Astaxanthin difatty acid ester usable in the present invention (concentration of total astaxanthin diesters in total weight 5.
An example of the fatty acid composition of the diester of 3% by weight, manufactured by Itano Frozen Co., Ltd. is shown below. However, the astaxanthin diester that can be used in the present invention is not limited to this. (In the following Examples and Comparative Examples, this product is simply abbreviated as astaxanthin diester unless otherwise specified.)

Comparative Example 1 (Stability Test) The following astaxanthin and its derivatives were compared for stability after heat treatment at 98 ° C. for 30 minutes. The titer after overheating was expressed in percentage with 100% before overheating. The titer was measured by the HPLC method.

Comparative Example 2 (Anti-inflammatory Effect on Carrageenan-Induced Paw Edema) A carrageenan-induced paw was obtained by subcutaneously administering 30 microliters physiological saline to the left paw of the mouse and the same amount of physiological saline containing 2% carrageenan to the right paw. Edema was induced and the paw volume change was measured after 4 hours. In the control group, 1 ml of 0.3% algin solution was used as an experimental group for aspirin 30.
0 mg / kg and 0.3% algin solution, astaxanthin diester 100 mg / kg and 0.3% algin solution, aspirin 100 mg / kg and astaxanthin diester 5 mg / kg and 0.3% algin solution 1 hour before carrageenan administration, respectively. The measurement was performed using orally administered mice.

[051]

Comparative Example 3 (Effect of aspirin on reducing side effects) 100 healthy men aged 29 to 53 were divided into two groups of 50, and one of them had aspirin 10 mg / k as a control.
g body weight, on the other hand, aspirin 10 mg / k as experimental group
g body weight and astaxanthin dipalmitate (purity 95% product) 5 mg / kg body weight as soft capsules without any notice 30 minutes after meal, orally administered 3 times a day for 3 days 3 times a day, loss of appetite, heartburn, stomachache, nausea, vomiting , Whether it caused tinnitus, deafness, dizziness, headache, agitation, hyperventilation, rash, edema, rhinitis-like symptoms, conjunctivitis, exfoliative dermatitis, etc. from the start of the test until 3 days after the end of the test . When any one of them had a symptom, the total score of 50 people in each ward was compared between the control ward and the experimental ward as 1 point, and the total score of 50 in the control ward was 57.
The total number of points and experimental plots was 35 points, and the side effect reducing effect of aspirin of astaxanthin dinister was confirmed.

Example 2 An anti-inflammatory drug was prepared by the usual method according to the following formulation. Chlorferamine maleate 0.5% Acetaminophen 20.5% Anhydrous caffeine 6.0% Acetylsalicylic acid 20.0% Carbetaventan citrate 3.0% Potassium guaiacol sulfonate 14.0% High propyl cellulose 9 0.0% Magnesium stearate 1.0% Astaxanthin diester 26.0%

Example 3 An anti-inflammatory gastrointestinal drug was produced by the usual method according to the following formulation. Cetraxate hydrochloride 10% Sodium bicarbonate 20% Takadiasucose 10% Synthetic hydrotalcite 15% Oat powder 5% Licorice powder 10% Astaxanthin diester 30%

Example 4 An anti-inflammatory cream was produced by a conventional method according to the following formulation. Squalane 10.0 Stearic acid 8.0 Stearyl alcohol 5.0 Beeswax 2.0 Propylene glycol monostearate 3.0 Polyoxyethylene cetyl ether 1.0 Astaxanthin diester 3.0 Propylene glycol 12.0 Paraben 0.2 Perfume 0 .5 Purified water residue

Example 5 An anti-inflammatory emulsion was prepared by a conventional method according to the following formulation. Avocado oil 10.0 Behenyl alcohol 0.5 Stearic acid 0.5 Glycerin fatty acid ester 1.0 Polyoxyethylene sorbitan fatty acid ester 1.0 Polyoxyethylene alkyl ether 0.5 Astaxanthin diester 3.0 Propylene glycol 10.0 Paraben 0. 2 Fragrance 0.5 Purified water Residual

Example 6 A soft capsule health food containing an anti-inflammatory agent was manufactured by a conventional method according to the following formulation. Fish oil containing EPA and DHA 40% Gelatin 17% Glycerin 5% Glycerin fatty acid ester 4% Beeswax 3% Vitamin E 1% Asxanthine diester 30%

Example 7 A tablet-like health food containing an anti-inflammatory agent was produced by a conventional method according to the following formulation. High propyl cellulose 9% White sugar 75% Magnesium stearate 1% Vitamin C 10% Astaxanthin diester 5%

Example 8 A granular health food containing an anti-inflammatory agent was produced by a conventional method according to the following formulation. Lactose 75% Starch 9% Vitamin C 4% Vitamin E 1% Gelatin 1% Astaxanthin diester 10%

Example 9 A hair nourishing agent containing an anti-inflammatory agent was produced by a conventional method according to the following formulation. Ethanol 60.0% Castor oil 4.0 Resorcinol 0.8 Methylparaben 0.1% Capsicum tincti 0.5% α-Tocopherol 0.5% Astaxanthin diester 0.5% Purified water Residue

Example 10 A shampoo containing an anti-inflammatory agent was produced by a conventional method according to the following formulation. Lauryl sulfate triethanolamine salt 16.0% Lauric acid diethanolamide 3.0% Polyacrylic acid triethanolamine salt 0.5% Zinc pyridinium-1-thiol-N-oxide 1.0% Astaxanthin diester 0.5% Dye Trace fragrance 0.5% Purified water Residue

Example 11 A rinse containing an anti-inflammatory agent was produced by a conventional method according to the following formulation. Stearyl dimethylbenzylammonium chloride 1.4% Stearyl alcohol 0.6% Glyceryl mosostearate 1.5% Sodium chloride 0.2% Astaxanthin diester 1.0% Purified water Residue

Example 12 An anti-inflammatory agent-containing bath agent was produced by a conventional method according to the following formulation. Sodium hydrogen carbonate 35.5% Citric acid 38.0% Polyethylene glycol 2.0% Magnesium oxide 1.0% α-tocopherol 0.5% Astaxanthin diester 25.0% Dye trace fragrance 2.0%

Example 13 A toothpaste containing an anti-inflammatory agent was produced by a conventional method according to the following formulation. Dicalcium phosphate dihydrate 45.0% Carboxymethylcellulose sodium 0.5% Carrageenan 0.5% Glycerin 10.0% Sorbitol 10.0% Saccharin sodium 0.1% Sodium lauryl sulfate 2.0% Sodium chloride 2 0.0% α-tocopherol 0.5% Astaxanthin diester 1.0% Preservative 0.1% Perfume 0.5% Purified water Residue

Example 14 A mouthwash containing an anti-inflammatory agent was produced by a conventional method according to the following formulation. Ethyl alcohol 35.0% Glycerin 14.0% α-Tocopherol 0.5% Askuxanthin diester 1.0% Perfume 0.1% Purified water Residue

Comparative Example 4 (Physical properties of astaxanthin diester) The astaxanthin diester-containing oil manufactured by Itano Frozen Co., Ltd. which can be used in the present invention was measured using a high performance liquid chromatogram under the following conditions. The retention time of the maximum peak of astaxanthin diester was measured. The time was 1 minute and 45 seconds, and the area ratio of the astaxanthins to the total area was 61.2%. In contrast, when conventional astaxanthin and astaxanthin monoester were measured under the same conditions, astaxanthin was 3 minutes 01 seconds and astaxanthin diester was 2 minutes 1
A maximum peak is obtained at 0 seconds and can be clearly separated from astaxanthin diesters.

High-performance liquid chromatogram measurement conditions: RPC Micro Bonder Pack NH ₂ (8 m
m. i. (dx100 mm) column, and the mobile phase was n-hexane: 2-propanol: methanol = 75:
15:15 using a flow rate of 2 ml / min. When the mobile phase was run at 470 nm with an ultraviolet-visible absorption spectrum detector
Was measured.

Comparative Example 5 (Inhibition of Lipid Peroxide by Topical Application) Charles River (CRT) ICR nude mice were divided into 2 groups, and one group was designated as a test group and the astaxanthin manufactured by Itano Frozen Co., Ltd. in the above-mentioned example was shown in the table below. Diester-containing anti-inflammatory composition 1.
Apply 0g to 2x4cm cotton gauze evenly 2
It was fixed at a fixed position on the dorsal side of 0 mice. As a control, a composition except for the astaxanthin diester alone was fixed in the same manner to the other group.
I replaced it with a new one at the same time and continued it for 14 days. Before this gauze exchange, 2 ml of a 2% aqueous solution of 2,2′-azobis (2-amidinopropane) dihydrochloride (hereinafter abbreviated as AAPH), which is a lipid peroxidation initiator, is used as an inflammation promoting substance. Soak in gauze of the same size as above once a day 3
I stuck on time. 14 days later, the concentration of lipid peroxide in the epidermis at the test site on the back of the mouse (hereinafter abbreviated as FBARS) was measured by the thioparbituric acid-reactive substance measurement method, and the ratio between the test plot and the control TBARS was calculated and the average values are summarized in the table below. It was As a result, it was suggested that the TBARS of the epidermis of the mouse to which the anti-inflammatory agent of the present invention, which is the test group, was attached was significantly lower than that of the control, and that the inflammation of the epidermis was prevented. The results of this comparative test confirmed the effect of the anti-inflammatory agent of the present invention.

[069]

Comparative Example 6 (Oral Lipid Peroxide Inhibitory Action) 10 mg / kg of AAPH as a 2% (W / V) aqueous solution was forcibly orally administered to Sprague-Dawley rats in the test group, and the health food and the anti-inflammatory drug of the above Examples were administered. In the control group, 20 mg / kg of the agent was orally administered by removing the astaxanthin diester from the examples. Free access to food and water. After 18 hours, TBARS of the small intestine was measured and the ratio between the test group and the control group was obtained in the same manner as in Comparative Example 1. As shown in the following table, the health food and anti-inflammatory agent of the present invention were found to have lipid peroxide inhibitory action, and the anti-inflammatory effect was confirmed.

[071]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location A61K 31/24 9455-4C 31/60 31/70

Claims (7)

[Claims] 1. An anti-inflammatory agent comprising an astaxanthin diester. 2. An anti-inflammatory agent, which comprises an astaxanthin diester extracted from krill. 3. Ascertaining the physical properties of astaxanthin diesters using a high performance liquid chromatogram, RPC Micro Bonder Pack NH ₂ (8 m
m. i. (dx100 mm) column, and the mobile phase was n-hexane: 2-propanol: methanol = 75:
15:15 using a flow rate of 2 ml / min. When the mobile phase was run at 470 nm with an ultraviolet-visible absorption spectrum detector
When the absorption of is observed, the retention time is from 0.5 minutes or more to 2
An anti-inflammatory agent comprising astaxanthin diesters capable of obtaining a maximum peak in the range of 30 seconds or less. 4. An anti-inflammatory agent, characterized in that diesters of astaxanthin diesters are blended with astaxanthin diesters composed of the same or different esters selected from fatty acid diesters and glycerophosphoric acid diesters. . 5. The same or different diesters of astaxanthin diesters selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), linoleic acid, linolenic acid, arachidonic acid, oleic acid, palmitic acid and stearic acid. An anti-inflammatory agent characterized by incorporating astaxanthin fatty acid diesters composed of different fatty acids. 6. A method of preventing side effects of a drug having side effects, which comprises blending astaxanthin diesters, and a drug having reduced side effects. 7. An aspirin preparation which is characterized by containing astaxanthin diesters and which has an increased effect of aspirin and reduced side effects of aspirin.