WO2007141898A1 - Ameliorant for eye strain - Google Patents

Abstract

An ameliorant for eye strain which contains as an active ingredient a compound having the ability to ameliorate eye strain; and a food or beverage for use in the prevention of or recovery from eye strain. The ameliorant and food or beverage for eye strain are characterized by containing as an active ingredient crocetin, which is represented by the formula, [Chemical formula 1] or a pharmacologically acceptable salt thereof.

Description

 Eye strain improving agent

 Technical field

 [0001] The present invention relates to an eye strain improving agent, food and drink, and a method for preventing or improving eye strain, comprising crocetin or a pharmacologically acceptable salt thereof as an active ingredient.

 Background art

 Eye strain refers to a state in which various subjective symptoms such as eye fatigue, eyes hurt, things are difficult to see, dizziness, and head ache are not resolved by rest. Causes of eye strain include power of eye overuse and mental tension caused by reading, gazing work, observation work, etc.In recent years, eye strain caused by VDT (Visual Display Terminal) work has been extremely high. Yes. There are still many uncertainties about the mechanism of the occurrence of eye strain. Force Eye strain is mostly regulated eye strain caused by abnormal regulation. It has been pointed out that accommodative eye strain occurs because ciliary muscles are in an excessively tensioned state due to long-term gaze work and the like, resulting in a decrease in the eye regulation function.

 [0003] Conventionally, for such eye strain, vitamin B, vitamin B, vitamin B, etc. have been included.

 1 6 12 The ophthalmic solution possessed is widely used. In addition, functional foods and drinks that can be easily ingested daily and are effective for eye fatigue include, for example, eye fatigue recovery agents containing anthocyanins extracted from mulberry (see Patent Document 1) and Nogikuhana. A novel compound, a functional food for improving eye strain containing Nogiku Flower Extract (see Patent Document 2), a functional food and drink containing Cassis Anthocyanin (see Patent Document 3), austaxanthin and Z Alternatively, foods and drinks (see Patent Document 4) having an effect of improving eye regulation dysfunction made of esters thereof have been proposed.

[0004] On the other hand, crocetin increases the blood flow in the retina of the rabbit and helps to restore the function of the retina (see Non-Patent Document 1) and the inflammation of the eye of the rabbit that is induced by PGE2. It has been reported to suppress the concentration dependently (see Non-Patent Document 2). However, the effect of crocetin on improving eye strain was unclear!

Patent Document 1: Japanese Patent Laid-Open No. 2001-178408, Claim 3 Patent Document 2: JP-A-11 246455, Claims 7 and 9

 Patent Document 3: International Publication No.01Z001798 Specification

 Patent Document 4: Specification of International Publication No.02Z094253

 Non-patent literature l: Xuan B, 4 others, “Effects of crocin analogs on ocular bio od flow and retinal functionj, Journal of Ocular Phamacology and Therapeutics, 1999, vol. 15, p. 143—152

 Non-Patent Document 2: Nagaki Y, 5 others, `` Effects of oral administration of Gard eniae Fructus extract and intravenous injection of Crocetin on lip ◦polysaccharide and prostaglandin E2— induced elevation of aqueou s flare in pigmented rabbitsj, The American Journal of Chinese M edicine, 2003, vol. 31, p. 729— 738

 Disclosure of the invention

 Problems to be solved by the invention

[0005] The present invention relates to an eye fatigue improving agent containing a compound having an eye fatigue improving effect as an active ingredient, a food or drink used for the prevention or recovery of eye fatigue, and the prevention or The purpose is to provide an improvement method.

 Means for solving the problem

[0006] As a result of intensive studies to solve the above problems, the present inventors have found that crocetin, which is a kind of carotenoid pigment, has an effect of improving eye strain, and based on this finding. The present invention was completed in a short time.

That is, the present invention provides:

 (1)

 Expression

で表されるクロセチンまたはその薬理学的に許容しうる塩を有効成分として含有する ことを特徴とする眼精疲労改善剤、 [Chemical 1]

A remedy for improving eye strain characterized by containing as an active ingredient crocetin represented by the formula:

 (2)

Expression

 [Chemical 2]

Containing as an active ingredient crocetin or a pharmacologically acceptable salt thereof, and labeled as being used for the prevention or recovery of eye strain

P

TO,

 (3) To produce foods and drinks for the purpose of preventing or recovering eye strain,

Expression

 [Chemical 3]

The use of crocetin represented by or a pharmaceutically acceptable salt thereof, and

 (Four)

Expression

 [Chemical 4]

Crocetin or a pharmacologically acceptable salt thereof is administered to a person who may cause eye strain or a person who has eye strain, or How to improve, It is made from.

 The invention's effect

 [0008] The eye strain improving agent and food and drink of the present invention have various symptoms of eye strain (for example, 1) eyes are tired, 2) eyes are painful, 3) eyes are hazy, 4) shoulders are stiff 5) Excellent effect in reducing head pain etc.

 By taking the eye strain improving agent or food or drink of the present invention before, during or after work causing eye strain, eye strain can be prevented or recovered. .

 BEST MODE FOR CARRYING OUT THE INVENTION

[0009] Crocetin used in the present invention,

 Expression

 [Chemical 5]

で表される化合物である。このクロセチンは、通常、カロテノイド系の黄色色素である クロシン (クロセチンのジゲンチオビオースエステル)を加水分解することにより得られ る。クロシンは、ァカネ科クチナシ（Gardenia augusta MERRIL var. grandifl ora HORT. , Gardenia jasminoides ELLIS)の果実、サフランの柱頭の乾燥 物などに含まれる力 クロシンを得るための工業的原料としてはクチナシの果実が好 ましく用いられる。

It is a compound represented by these. This crocetin is usually obtained by hydrolyzing crocin (a digentiobiose ester of crocetin), which is a carotenoid yellow pigment. Crocin is the power of gardenia augusta MERRIL var. It is used well.

[0010] In the present invention, there is no limitation on the method for extracting the above-mentioned plant basic force crocin, for example, dried fruit strength of ground gardenia water or alcohol (eg, methanol, ethanol, etc.), or A known method such as extraction using a mixed solution thereof is used. For example, when using a mixture of water and alcohol, the extraction condition at this time is about 30 to 40 ° C, which is about 1 to 18 hours at room temperature (about 0 to 30 ° C) to 50 ° C. ~ 4 hours is more preferred. The extraction operation is usually repeated several times. Crocin obtained Next, a solution obtained by dissolving an extract containing lysate, a concentrated solution of the extract or a concentrated dried product in an appropriate solvent (for example, water or ethanol) is then subjected to a hydrolysis step.

 [0011] Hydrolysis of crocin may be carried out according to a conventional method, and is usually carried out in the presence of acid, alkali or a suitable hydrolase. Examples of the acid include hydrochloric acid, sulfuric acid, and phosphoric acid, and examples of the alkali include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate. Examples of hydrolases include β-darcosidase. The acid, alkali or enzyme is preferably added to a solution containing crocin after being dissolved or dispersed in a suitable solvent (eg, water or ethanol).

 [0012] Industrially, crocin is preferably hydrolyzed in the presence of an alkali.

 The hydrolysis conditions are not particularly limited, but with stirring, preferably at about 20 to 70 ° C for about 1 to 24 hours, particularly preferably at about 40 to 60 ° C for about 3 to 5 hours. It is.

 [0013] When the hydrolysis of crocin is hydrolysis with an alkali, usually, after completion of the hydrolysis, an appropriate amount of an aqueous solution of an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or an organic acid such as cuenic acid is added to the reaction solution. In addition, the solution is adjusted to pH 4 or less, preferably about pH 1 to 3, or the reaction solution is added to an aqueous solution of an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or an organic acid such as citrate. The crocetin can be precipitated by adjusting the pH to about 4 or less, preferably about pH 1 to 3. Thereafter, the crocetin can be recovered as a pasty solid by centrifuging the mixture or filtering through a filter paper or filter cloth.

 [0014] When crocin is hydrolyzed with acid, the produced crocetin precipitates in a free form insoluble in water, and thus the reaction solution is obtained as a suspension. After completion of the reaction, crocetin can be recovered as a pasty solid by centrifuging the obtained suspension or filtering through a filter paper or filter cloth.

[0015] Crocetin (paste-like solid) obtained as described above usually has acid, neutralized salt, and impurities derived from raw materials attached to the surface of the solid, so that the impurities are removed. A cleaning process is performed for the purpose. The treatment may be performed using a known method, for example, washing the pasty solid with a sufficient amount of water. Next, for example, shelf type The solid material washed with water, for example, is dried at a temperature not exceeding about 50 ° C. in an atmosphere of nitrogen gas, for example, by using an air dryer or a vacuum dryer, and the water remaining on the solid material is removed. preferable.

 [0016] However, even the crocetin thus obtained is produced by hydrolysis of substances other than crocetin, such as lipids and their degradation products, polyphenols such as chlorogenic acid, and washing. It is preferable to further purify the crocetin since it may contain saccharides such as glucose and gentiobiose that are not completely removed. Here, the method for purifying the crocetin is not limited, and known methods such as column chromatography and recrystallization are used.

 [0017] The crocetin used in the present invention is crocetin having a purity of about 70% by mass or more, preferably crocetin having a purity of about 90% by mass or more, more preferably having a purity of about 95% by mass or more. Most preferably. Here, the purity of crocetin is calculated based on the color value of pure crocetin. The color value is a value measured by the [color value measuring method] described in Examples below.

 In the present invention, pharmacologically acceptable salts of crocetin include, for example, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium and calcium, pyridine, dimethylamine, jetylamine, ethanol And pharmaceutically acceptable salts of organic amino compounds such as min.

 [0019] Since crocetin, which is effective in the present invention, has an effect of improving eye strain, it is used as an eye fatigue improving agent containing the crocetin or a pharmacologically acceptable salt thereof as an active ingredient, or for preventing eye fatigue. Or it is useful as a food or drink for the purpose of recovery.

[0020] The eye fatigue-improving agent of the present invention and the food and drink used for preventing or recovering eye fatigue are used as such or pharmaceutically acceptable for the crocetin or a pharmacologically acceptable salt thereof. Additives, food ingredients, food ingredients, and if necessary, food additives, etc., as appropriate, and in accordance with conventional methods, for example, liquid preparations, powders, granules, tablets, microcapsules, soft capsules, hard capsules, etc. Manufactured as a product. In addition, a crocetin-containing composition such as an oil or fat composition mainly composed of crocetin or a pharmacologically acceptable salt thereof, an oZw type emulsion, a wZo type emulsion or a soluble salt solution. The food or drink of the present invention may be produced by producing a product according to a conventional method and adding this crocetin-containing composition to food or drink.

 [0021] The food and drink can take any food form such as a solid food, a cream-like or jam-like semi-solid food, a gel food, and a beverage. Examples of food and drink include soft drinks, drops, candy, chewing gum, chocolate, gummi, yogurt, ice cream, pudding, jelly confectionery, cookies, margarine, shortening, mayonnaise and dressing. The foods and beverages mentioned above prevent specific health foods with the indication that they are used for the prevention or recovery of eye strain, or the accumulation of eye strain and various symptoms associated therewith. It is also useful as a health food intended to recover.

 [0022] Additives, food materials, food ingredients and food additives used in the preparation of the above-mentioned preparations and foods and drinks include, for example, excipients (lactose, dextrin, corn starch, crystal cell mouth etc.), lubricants, etc. Agents (magnesium stearate, sucrose fatty acid ester, glycerin fatty acid ester, etc.), disintegrating agents (carboxymethylcellulose calcium, anhydrous calcium phosphate, calcium carbonate, etc.), binders (starch glue, hydroxypropyl cellulose) , Gum arabic liquid, etc.), solubilizers (gum arabic, polysorbate 80, etc.), sweeteners (sugar, fructose, glucose liquid sugar, honey, aspartame, etc.), coloring agents () Riboflavin), preservatives (such as sorbic acid, methyl parabenzoate, sodium sulfite) ), Thickeners (sodium alginate, sodium carboxymethylcellulose, sodium polyacrylate, etc.), anti-oxidants (dibutylhydroxytoluene (BHT), butylhydroxy-sol (BHA), ascorbic acid, Tocopherols, etc.), flavors (such as heart force, strawberry flavors), sour seasonings (taenoic acid, lactose, DL—malic acid, etc.), seasonings (DL—alanin, sodium 5′-inosinate, sodium L—glutamate) Etc.), emulsifiers (glycerin fatty acid esters, sucrose fatty acid esters, etc.), pH adjusters (taenoic acid, trisodium citrate, etc.), vitamins, minerals, amino acids and the like.

[0023] In the case of the above-mentioned preparation, the content of crocetin or a pharmacologically acceptable salt thereof varies depending on the symptoms of eye strain, its purpose, use, etc., but is not uniform. In contrast, in terms of crocetin purity 100 mass _^0/0, usually about 0.0001 to 50 weight _^0/0, good Mashiku about 0.001 to 20 wt%, more preferably about 0.01 to 10 % By mass.

[0024] In the case of the above food and drink, the content of crocetin or a pharmacologically acceptable salt thereof is usually about 0 in terms of crocetin having a purity of 100% by mass with respect to the total mass of the food or drink. . 00003-10 weight _^0/0, preferably from about 0.01 to 5 weight _^0/0, more preferably from about 1 to 5 mass%.

 [0025] When the above preparations and foods and drinks are taken orally, the adult dose of crocetin or a pharmacologically acceptable salt thereof (about 60 kg) The daily dose should be converted to crocetin with a purity of 100% by mass. In general, it is in the range of about 0.1 to 500 mg, preferably about 1 to 200 mg, more preferably about 2 to 50 mg. This dose may be taken in one or several divided doses. However, the actual dose should be determined in consideration of the purpose and intake situation (degree of eye strain, gender, age, health status, etc.).

 [0026] In addition, in the case of parenterals such as injections or infusions, adults (about 60 kg) per day, converted to crocetin with a purity of 100% by mass, crocetin or its pharmacologically acceptable Desirable salt should be set to a dosage of about 0.1 Olg to: LOOmg, preferably about 0.1 to 50 mg, more preferably about 0.1 to 15 mg.

 [0027] Further, the eye strain improving agent of the present invention can be used in combination with other drugs or supplements for the purpose of recovery from eye strain. Examples of such drugs and supplements include vitamins (for example, vitamin A, vitamin B, vitamin B, vitamin B, vitamin B, vitamin C, vitamin B).

 1 2 6 12

 Tamine E, nicotinamide, pantothenic acid, etc.), amino acids (eg, taurine, aspartic acid or its salts), anthocyanins (eg, strawberry concentrate, cranberry juice, black chokeberry juice, blueberry juice) , Plum concentrated juice, etc.) and caffeine.

[0028] The method for preventing or ameliorating eye strain according to the present invention causes crocetin or a pharmacologically acceptable salt thereof to occur in a person, particularly a person who may cause eye strain or eye strain. It is a method to administer to a person. Examples of the person who may cause eye strain include a person who looks at a display such as a computer or a TV for a long time in daily life. In the present invention, for the prevention of eye strain, suppression of the onset of eye strain and Inhibiting the progression of eye strain. The dosage and administration method of crocetin or a pharmacologically acceptable salt thereof are as described above.

 Example

 [0029] Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited thereto.

[0030] [Preparation of crocetin]

 (1) Methanol-water mixture (1: 1) (V / V) (600 mL) was added to 300 g of dried dried fruit of gardenia and stirred at room temperature for 3 hours, followed by suction filtration. After filtration, add 600 mL of methanol / water mixture (1: 1) (VZV) to the extraction residue, stir at room temperature for 30 minutes, and repeat suction filtration twice to obtain a total of about 1800 mL of extract as filtrate. Obtained. This extract was concentrated using a rotary evaporator at about 60 ° C. and about 4 kPa, to obtain about lOOg of a concentrate (color value = about 573) containing crocin.

 (2) The concentrate obtained in the above (1) was mixed with 34 g of a 40% by mass aqueous sodium hydroxide solution and subjected to a hydrolysis reaction at 50 ° C. for about 3.5 hours with stirring. After completion of the reaction, the reaction solution was acidified by adding 840 mL of a 4% by mass phosphoric acid aqueous solution, and then allowed to stand at room temperature for about 3 hours.

(3) Collect the precipitate deposited by the above-mentioned solution (2) by centrifugation (10,000 X g, 10 minutes), wash with 200 mL of water, and centrifuge twice to obtain The obtained pasty solid was vacuum-dried at 50 ° C. for about 8 hours.

 (4) The above operations (1) to (3) were repeated 5 times, and the obtained crystals were collected into one to obtain about 12 g of crude crocetin. The color value of this was about 12,500.

 [0031] [Preparation of purified crocetin]

 To about 10 g of the crude crocetin obtained above, 180 mL of dimethylformamide was added and dissolved at 80 ° C. Insoluble matter was filtered through quantitative filter paper (No. 5C, manufactured by Advantech Toyo Co., Ltd.), and the filtrate was left at 10 ° C. for 3 days. Next, the mother liquor containing the produced crocetin crystals is filtered through a glass filter (trade name: 3G3; manufactured by Shibata Kagaku, pore size 40-100 μm), washed with 200 mL of methanol, and then the crystals are vacuumed at 50 ° C. After drying, about 1.6 g of purified crocetin (prototype) was obtained. The color value of this was 34,200.

[0032] [Purity of crocetin] About 0.5 g of purified crocetin (prototype) was recrystallized with dimethylformamide, and the resulting crocetin crystals (color value 35, 700) were defined as “pure crocetin”. The purity of crocetin was calculated.

[0033] [Equation 1] Color value of crocetin

 Crocetin purity (%) = X I 0 0

 3 5 7 0 0

[0034] The purity of the purified crocetin (prototype) calculated based on the above formula was 95.8%.

 The color value (Ε) is “Food Additives other than Chemical Synthetic Products Voluntary Standard (Second Edition)”, day lcm

 Measured by the following method with reference to “Kuchinashi Ajimoto” edited by this Food Additives Association.

[0035] [Color value measurement method]

 Weigh accurately the sample so that the absorbance to be measured is in the range of 0.3 to 0.7, and dissolve in Kolthoff's buffer solution (50 mM Na CO 50 mM Na B O, ρΗΙΟ. 0).

 2 3 2 4 7

 Oml. If it is difficult to dissolve, dissolve by sonication. Weigh exactly 10 ml and add Kolthoff's buffer (50 mM Na CO—50 mM Na B 2 O, ρΗΙΟ. 0).

 2 3 2 4 7

 Use 50 ml as the test solution. Mr. Kolthoff buffer (50 mM Na CO-50 mM Na B

 2 3 2

O, pHlO. 0) as a control, and the liquid layer length lcm is at the maximum absorption part around 420 nm.

4 7

 Absorbance A was measured, and the color value was determined by the following formula.

[0036] [Equation 2]

A X 2 5 0

Color value (E, ^{0 ¾} , _cm ) = X 1 0 0

 Amount of sample collected (g)

[0037] [Test Example 1]

 In order to evaluate the improvement effect of crocetin on eyestrain, two types of capsules (250mgZl capsules) filled with the contents shown in Table 1 were prepared and engaged in VDT work. Targeting healthy adult males (30 to 40 years old) who are aware of symptoms of eye strain such as eye fatigue after work, subjects were tested (n = 10) and control (placebo) groups ( A double-blind study was randomly assigned to n = 10).

[0038] [Table 1] Test drug Control drug

 Purified crocetin (prototype) 8. 4 0. 0

Lactose ¹ ) 2 3 1 .6 2 4 0 .0

Pullulan ²⁾ 6. 0 6. 0

Polydaricelin fatty acid ester ³ > 4.0 4.0

 2 5 0. 0 2 5 0. 0

 The unit of numerical values in Table 1 is mg.

¹ > Product name: Flow rack; Sanfco

² ) Hayashibara

³⁾ Product name: Poem TR—FB: Riken Vitamin

[0039] <Test method>

 After subjecting 20 subjects to VDT work continuously for 3 hours, subject's subjective symptoms associated with eye strain were as follows: 1) eyes are tired, 2) eyes are painful, 3) eyes are hazy, 4) For the five items of stiff shoulders and 5) head pain, use the visual analog scale method to fill in a line on a 10cm line segment from 0 (not felt) to 10 (extremely felt). It was.

 Next, subjects took 1 capsule of the test drug or control drug (placebo), and after 1 hour of taking the subject, the degree of subjective symptoms accompanying eye strain of the subject was entered again.

 For each subject, the average value of the five items at the end of the work and the average value of the five items one hour after taking the dose were calculated, and the degree of improvement in symptoms was calculated based on the following formula: .

[0040] [Equation 3]

 B

 Improvement factor = 1

 A

 A: Average value of 5 items at the end of work

 B: Average value of 5 items 1 hour after taking

[0041] <Result>

 The numerical values of improvement were tabulated for each test drug group and the control drug (placebo) group, and the average value of the improvement degree of 10 subjects in each group was calculated. The results are shown in Table 2. As a result of testing the difference of the population mean between the control drug (placebo) group and the test drug group by Dunnet method, the difference was statistically significant (risk rate 5%).

This result shows that the eye strain improving agent of the present invention is effective for recovery from eye strain. [0042] [Table 2]

 *: P 0.05 V s Control (placebo) group

[0043] [Test Example 2]

 In order to evaluate the improvement effect of crocetin on eye strain, two types of capsules (180mgZl capsule) filled with the contents shown in Table 3 were prepared, and eye fatigue symptoms such as eye strain were recognized. A double-blind crossover study was conducted on healthy adult males and females (aged 25-40).

[0044] [Table 3]

 The unit of numerical values in Table 3 is mg.

 1) Purified crocetin (Brand name: Crocetin P;

 (Riken Vitamin, purity 75%)

 2) Dextrin (Brand name: Paindex # 6;

 (Matsuya Chemical Co., Ltd.)

<Test method>

 Thirteen subjects were randomly assigned to group A (n = 7) and group B (n = 6). Group A was the test drug administration group and group B was the control drug administration group. After subjecting each subject to VDT work continuously for 1 hour, the degree of adjustment tension of the ciliary muscle was measured using an adjustment function analysis device (AA-1; manufactured by Nidec Co.), and the measured value obtained The appearance frequency (HFC) of force-adjusted microtremor was calculated. After resting after resting for 20 minutes, the measurement power HFC obtained was calculated, and the difference in HFC value before and after rest was also calculated for the change in HFC before each group intake. Thereafter, the test drug was administered to Group A, the control drug was administered to Group B, 1 capsule daily, after breakfast, and the above test was conducted 4 weeks later to determine the amount of HFC change after each group intake.

After taking a 6-week washout period, the same study was conducted with Group A as the control drug administration group and Group B as the test drug administration group.Changes in HFC before and after intake in each group The Asked.

 [0046] <Result>

 For each test drug administration group and control drug (placebo) administration group, the HFC change before intake and the HFC change after intake were totaled, and the average value of the HFC change of 13 subjects in each group was calculated. The results are shown in Table 4.

 Based on the aggregated data of each group, a paired t-test was performed. As a result, there was a significant difference in the comparison between the following two groups.

Test drug administration group (before ingestion) _vs Test drug administration group (after ingestion): Risk factor 5%

Test drug administration group (after ingestion) _vs. control drug administration group (after ingestion): Risk 1%

 This result indicates that the eye strain improving agent of the present invention is effective for recovery from eye strain.

[0047] [Table 4] HFC change before ingestion HFC change after ingestion Test drug administration group 1.6 3 ± 5. 9 9 1 2. 9 1 Sat 5.4 6 Control group administration 3.7 8 ± 6. 6 8 0. 4 8 ± 7. 2 5

Claims

The scope of the claims  Expression

 Or a pharmacologically acceptable salt thereof as an active ingredient. [2] Expression  [Chemical 2]

 Containing as an active ingredient crocetin or a pharmacologically acceptable salt thereof, and labeled as being used for the prevention or recovery of eye strain P PPo  [3] To produce foods and drinks for the purpose of preventing or relieving eye strain,  Expression [Chemical 3]

 Or a pharmacologically acceptable salt thereof. [4] Expression [Chemical 4]

Crocetin or a pharmacologically acceptable salt thereof is administered to a person who may cause eye strain or a person who has eye strain, or How to improve.