CN116744936A

CN116744936A - Lens hardness modifier

Info

Publication number: CN116744936A
Application number: CN202180077019.4A
Authority: CN
Inventors: 中泽洋介; 森下尚纪; 远藤伸; 三宅正树; 三鼓仁志; 早野元词; 坪田一男
Original assignee: Hayashibara Co Ltd; Tsubota Laboratory Inc
Current assignee: Hayashibara Co Ltd; Tsubota Laboratory Inc
Priority date: 2020-11-17
Filing date: 2021-11-15
Publication date: 2023-09-12

Abstract

The present invention addresses the problems by providing a novel lens hardness regulator which can be easily, simply, safely and effectively regulate the hardness of the lens for a long period of time, and can prevent, alleviate and improve focal dysregulation such as presbyopia and myopia vision deterioration caused by aging and various diseases, and by providing a lens hardness regulator containing glycosyl hesperetin as an active ingredient.

Description

Lens hardness modifier

Technical Field

The present invention relates to a lens hardness adjuster containing glycosyl hesperetin as an active ingredient, and more specifically, to a lens softener or a lens hardening inhibitor.

Background

Presbyopia is considered to occur in all people over 40 years old, and it is presumed that 6500 tens of thousands of people exist in japan and 18 hundreds of millions of people exist in the world. In modern aging society, presbyopia is regarded as a problem directly related to Quality of life (QOL), and effective measures against presbyopia are expected. Further, in recent years, not only the typical presbyopia that occurs with age, but also younger presbyopia, that is, presbyopia that is difficult to adjust even for children of lower ages, is becoming more important to say that symptoms of presbyopia are being described, and development of a method of countermeasure against presbyopia that can be easily and safely applied to people of all ages is increasing.

Presbyopia is a condition in which the strength of adjusting the focus of the eye is reduced, which causes difficulty in looking at something in close proximity, and typically occurs with age, and is also commonly referred to as "presbyopia". The lens of the eye is a tissue that refracts light, and when looking far, the muscles around the lens (ciliary muscles) relax, reducing the thickness of the lens, whereas when looking near, the thickness of the lens increases by contraction of the ciliary muscles, focusing. However, due to age, etc., the muscular strength of the ciliary body is lowered, the crystalline lens itself is hardened to lose elasticity, and thus it is difficult to adjust the focus, particularly the near vision (myopia vision) is lowered.

That is, it is considered that by properly adjusting and maintaining the elasticity of the lens, it is possible to prevent, alleviate and improve the focal adjustment failure such as presbyopia and the like and the decline of myopia.

As measures against presbyopia, correction by presbyopia glasses, presbyopia contact lenses, or the like is generally given as an option. However, in life using presbyopic glasses and contact lenses, there is a trouble of wearing and taking them, and if presbyopia is prevented, alleviated, and improved by daily intake of supplements, QOL is significantly improved, for example.

Under such circumstances, in recent years, various techniques for adjusting the hardness of the lens have been reported. For example, there are reported anti-hardening agents and therapeutic agents for lens tissues using various physiologically active substances such as cytokines obtained by culturing mesenchymal stem cells (patent document 1). Further, there have been reported a lens hardening inhibitor containing pirenoxine or a salt thereof and/or tiopronin or a salt thereof, and a therapeutic and/or prophylactic agent for a disease associated with lens hardening (patent document 2), a lens hardening inhibitor containing a selenium compound such as selenolactone or a salt thereof as an active ingredient, and a therapeutic and/or prophylactic agent for a disease associated with lens hardening (patent document 3), and a pharmaceutical composition for the prophylaxis and/or treatment of keratoconjunctival disease or presbyopia containing a stilbene compound as an active ingredient (patent document 4). However, these drugs are medicines, and there is a disadvantage that they cannot be easily and simply taken for a long period of time.

Prior art literature

Patent literature

Patent document 1: japanese patent laid-open No. 2019-156742

Patent document 2: international publication 2016-068278 pamphlet

Patent document 3: japanese patent application laid-open No. 2015-140327

Patent document 4: international publication 2016-031869 pamphlet

Disclosure of Invention

Problems to be solved by the invention

The present invention has been made in view of the above-described conventional techniques, and an object of the present invention is to provide a novel lens hardness adjuster which can be easily, simply, safely and effectively adjust the hardness of the lens for a long period of time, and which can prevent, alleviate and improve focal dysregulation such as presbyopia and myopia vision deterioration.

Means for solving the problems

As a result of intensive studies to solve the above-mentioned problems, the present inventors have unexpectedly found that the hardness of a lens is adjusted by orally taking glycosyl hesperetin, and in detail, the hardness of the lens is suppressed and the temporarily hardened lens is softened, thereby completing the lens hardness adjustment agent of the present invention.

That is, in one embodiment, the present invention solves the above-described problems by providing a lens hardness adjuster containing glycosyl hesperetin as an active ingredient.

ADVANTAGEOUS EFFECTS OF INVENTION

The lens hardness adjuster according to one embodiment of the present invention is a lens hardness adjuster containing glycosyl hesperetin as an active ingredient, can be orally taken and the like safely and easily for a long time without discomfort, and can be industrially provided at low cost. In one embodiment, the lens hardness adjuster according to the present invention can effectively suppress hardening of the lens and can soften the temporarily hardened lens.

Drawings

Fig. 1 is a graph showing the change with time of the body weight of a test mouse when a test sample and a control sample containing glycosyl hesperetin are taken for 16 weeks.

FIG. 2 is a graph showing the cumulative amount of water intake in mice tested when the test sample and the control sample containing glycosyl hesperetin were ingested for 16 weeks.

Fig. 3 is a graph showing the cumulative amount of intake of the test mice when the test sample and the control sample containing glycosyl hesperetin are taken for 16 weeks.

Fig. 4 is a graph showing the change with time in the body weight of a test mouse when a test sample and a control sample containing glycosyl hesperetin are taken for 28 weeks.

Fig. 5 is a graph showing the cumulative amount of water intake of the test mice when the test sample and the control sample containing glycosyl hesperetin were taken for 28 weeks.

Fig. 6 is a graph showing the cumulative amount of intake of the test mice when the test sample and the control sample containing glycosyl hesperetin were taken for 28 weeks.

Fig. 7 is a graph showing the change with time in the body weight of a test mouse when the test sample and the control sample containing glycosyl hesperetin are taken for 10 weeks.

Fig. 8 is a graph showing the cumulative amount of water intake of the test mice when the test sample and the control sample containing glycosyl hesperetin were taken for 10 weeks.

Fig. 9 is a graph showing the cumulative amount of intake of the test mice when the test sample and the control sample containing glycosyl hesperetin were taken for 10 weeks.

Fig. 10 is a graph showing the change with time in the body weight of a test mouse when a test sample and a control sample containing glycosyl hesperetin are taken for 15 weeks.

Fig. 11 is a graph showing the cumulative amount of water intake of the test mice when the test sample and the control sample containing glycosyl hesperetin were taken for 15 weeks.

Fig. 12 is a graph showing the cumulative amount of intake of the test mice when the test sample and the control sample containing glycosyl hesperetin were taken for 15 weeks.

Fig. 13 is a graph showing the amount of change in myopia vision of a person (aged 40 years) when a test sample and a control sample containing glycosyl hesperetin are taken for 3 months.

Fig. 14 is a graph showing the amount of change in myopia vision of a person (second half of 40 years old) when a test sample and a control sample containing glycosyl hesperetin are taken for 3 months.

Detailed Description

Embodiments of the present invention will be described below, and these preferred embodiments are merely examples of the practice of the present invention, and the present invention is not limited to these embodiments.

In one aspect, the present invention relates to a lens hardness adjuster containing glycosyl hesperetin as an active ingredient and a method for adjusting the hardness of a lens characterized by using glycosyl hesperetin as an active ingredient.

The hardness of the lens in the present specification means the degree of hardness of the lens, and specifically, the hardness is evaluated by the magnitude of the load when the lens is subjected to a certain amount of dishing, which is shown in experiments described later. That is, hardening of the lens means an increase in hardness of the lens, in other words, a load when a certain amount of concavity is generated in the lens becomes large.

By lens hardness adjustment in the present specification is meant inhibiting hardening of the lens or softening the temporarily hardened lens.

The term "lens hardening inhibition" as used herein means a preparation for inhibiting the progress of hardening of the lens to maintain the hardness of the lens, which is caused by various factors such as aging and diseases, and means preventing the hardening of the lens or alleviating the progress of hardening of the lens. The softening of the lens in the present specification means that the hardness of the lens becomes small, and the lens softener means an agent that improves the hardening of the lens, reduces the hardness of the lens, or treats symptoms caused by the hardening of the lens.

The glycosyl hesperetin used as the active ingredient of the lens hardness modifier of the present application contains all compounds in which saccharide binds to hesperetin, and in one embodiment, 1 or 2 or more kinds selected from hesperidin, α -glycosyl hesperidin, and 7-O- β -glycosyl hesperetin are exemplified as suitable specific examples thereof.

Hesperidin, also called vitamin P, is a compound represented by the structural formula shown in the following chemical formula 1, which has a structure in which rutinoside composed of rhamnose and glucose binds to hesperetin, and is a component contained in a large amount in the pericarp of citrus.

Chemical formula 1:

[ chemical 1]

In addition, 7-O- β -glucosyl hesperetin is a compound represented by the following chemical formula 2, which has a structure in which a rhamnosyl group of rutinoside is detached, and has a characteristic of higher water solubility than hesperidin. For example, as shown in Japanese patent application laid-open No. 10-323196, 7-O-beta-glucosyl hesperetin can be produced by allowing alpha-L-rhamnosidase (EC 3.2.1.40) to act on a hesperidin-containing solution.

Chemical formula 2:

[ chemical 2]

Furthermore, α -glycosyl hesperidin is a compound in which saccharides (e.g., saccharides such as D-glucose, D-fructose, and D-galactose) are α -bonded to hesperidin in equal molar amounts or more. As a representative example of the alpha-glycosyl hesperidin, there may be mentioned alpha-glycosyl hesperidin represented by the following chemical formula 3 (alias: enzyme-treated hesperidin, glycosyl-transferred hesperidin, water-soluble hesperidin, or glycosyl-transferred vitamin P) which is formed by binding glucose 1 molecule to glucose alpha-1, 4 in the rutinose structure of hesperidin. As the product containing α -glucosyl hesperidin, for example, the trade name "linn former hesperidin S" (sold by Pron Co., ltd.) is commercially available.

Chemical formula 3:

[ chemical 3]

Glycosyl hesperetin has been widely used as a raw material for various foods, drinks, cosmetics, quasi drugs, medicines, and the like, and has high safety and versatility. Among them, α -glycosyl hesperidin has higher water solubility and excellent handleability than hesperidin and 7-O- β -glycosyl hesperetin, and is hydrolyzed to hesperetin by an in vivo enzyme in the same manner as hesperidin and 7-O- β -glycosyl hesperetin, thereby exerting the original physiological activity of hesperetin.

In the present invention, the glycosyl hesperetin may be any glycosyl hesperetin, and may be used regardless of its source, production method, purity, etc., and in any suitable manner, a high purity product having fewer impurities may be suitably used. The high-purity product may include, for example, high-purity glycosyl hesperetin obtained by crystallization and purification by chromatography.

The hesperidin can be industrially produced in a desired amount by, for example, extracting a citrus fruit, pericarp, seed, immature fruit, or the like, which is a plant containing hesperidin, with a solvent such as water or alcohol as appropriate. In addition, as disclosed in, for example, japanese patent application laid-open No. 11-346792, a glycosyltransferase is allowed to act on a solution containing hesperidin and an alpha-glucosyl saccharide compound to produce alpha-glycosyl hesperidin, which is collected, whereby a desired amount of the alpha-glycosyl hesperidin can be industrially produced at low cost. Further, 7-O- β -glucosyl hesperetin can be produced by allowing α -L-rhamnosidase to act on hesperidin, thereby freeing rhamnose from hesperidin, and collecting it, whereby a desired amount thereof can be industrially produced at low cost.

In addition, the same applicant as the present application has established that by improving the production method thereof, for the purpose of eliminating unpleasant taste, coloring, etc. which have been conventionally considered as drawbacks of glycosyl hesperetin, the glycosyl hesperetin and the production method thereof are disclosed in the pamphlet of international publication No. 2015/133483, in which the unpleasant taste and coloring are reduced from nothing more than odor (hereinafter, the "unpleasant taste, coloring, and odor" may be collectively referred to as "unpleasant taste, etc.). The glycosyl hesperetin with reduced unpleasant taste has excellent advantages such as being safe and easy to orally ingest by a person on a daily basis, and being industrially provided at low cost. Therefore, the above glycosyl hesperetin with reduced unpleasant taste and the like can be advantageously used as a suitable glycosyl hesperetin in a suitable embodiment of the present application.

In the present specification, in the case of simply called glycosyl hesperetin, it is sometimes meant to include a mixture of glycosyl hesperetin of 1 or 2 or more kinds selected from hesperidin, α -glycosyl hesperidin and 7-O- β -glycosyl hesperetin unless otherwise specified. In a preferred embodiment, the glycosyl hesperetin used as the active ingredient preferably contains α -glycosyl hesperidin, and from the viewpoint of more significantly exerting the desired action effects of the present application, that is, the effects of lens hardening inhibition, lens softening, etc., it is more preferable to contain α -glycosyl hesperidin as α -glycosyl hesperidin.

As described above, in one embodiment, the glycosyl hesperetin contained as an active ingredient of the crystalline lens hardness modifier of the present invention may be a composition containing, as main ingredients, 1 or more selected from (1) hesperidin, α -glycosyl hesperidin (α -glucosyl hesperidin, etc.) and 7-O- β -glycosyl hesperetin, which are compounds having a hesperetin skeleton, that is, a glycosyl hesperetin mixture, and may further contain (2) flavonoid such as rutin, myrtillin, melissa glycoside, glucosyl naringin, etc., and (3) a trace ingredient such as salts, which are considered to be derived from a raw material for production thereof or as by-products in a production process thereof. In one embodiment, the glycosyl hesperetin contained as the active ingredient of the lens hardness modifier according to the present invention may include hesperetin in a range that does not interfere with the desired effect of the present invention, and hesperetin having improved dispersibility in a solvent such as water by a known physical or chemical method or the like.

In one embodiment, the total content of glycosyl hesperetin per dry solid matter is usually 50% by mass or more and less than 100% by mass, preferably 60% by mass or more and less than 100% by mass, more preferably 70% by mass and less than 100% by mass, still more preferably 80% by mass and less than 100% by mass, still more preferably 85% by mass and less than 100% by mass, in the glycosyl hesperetin or glycosyl hesperetin mixture contained as an active ingredient of the lens hardness modifier of the present invention. In one embodiment, the upper limit of the content of glycosyl hesperetin per dry solid matter contained in the glycosyl hesperetin or glycosyl hesperetin mixture as an active ingredient of the lens hardness modifier according to the present invention may be generally 99 mass% or less, 98 mass% or less, and 97 mass% or less, which can be provided in a relatively large amount, low cost and easy manner industrially. However, in the case where the content of the glycosyl hesperetin per unit dry solid substance of the glycosyl hesperetin or glycosyl hesperetin mixture is low, the glycosyl hesperetin is inevitably used in a large amount, and as a result, the operation becomes complicated and the handling property becomes poor, and therefore, in a suitable embodiment, the lower limit of the glycosyl hesperetin content is preferably 50 mass% or more, preferably 60 mass% or more, more preferably 70 mass% or more, further preferably 80 mass% or more, and still more preferably 85 mass% or more.

The glycosyl hesperetin content in the present application means the sum of the contents of each component corresponding to glycosyl hesperetin in the composition converted to the mass of anhydride, calculated from the area of peaks appearing in the chromatograph at UV280nm and the molecular weight of each component such as hesperidin, α -glycosyl hesperidin (α -glycosyl hesperidin, etc.), in the composition, which was diluted or dissolved with purified water so that the solid concentration became 0.1% (w/v), and filtered with a 0.45 μm membrane filter, and then analyzed by High Performance Liquid Chromatography (HPLC) under the following conditions, using reagent hesperidin (Fuji film and light purity chemical Co., ltd.) as a standard substance. The quantitative method of the content of each component corresponding to glycosyl hesperetin by HPLC analysis is as shown in (1) to (4) below, for example.

< HPLC analysis conditions >)

HPLC apparatus: "LC-20AD" (manufactured by Shimadzu corporation)

A degasser: "DGU-20A3" (manufactured by Shimadzu corporation)

Chromatographic column: "CAPCELL PAK C UG 120" (manufactured by Kagaku-Toku-shou-Kogyo Co., ltd.)

And (3) detection: UV detector "SPD-20A" (manufactured by Shimadzu corporation)

A data processing device: "CHROMATOPAC C-R7A" (manufactured by Shimadzu corporation)

Sample injection amount: 10 mu L

Eluent: water/acetonitrile/acetic acid (80/20/0.01 (volume ratio))

Flow rate: 0.7 mL/min

Temperature: 40 DEG C

Measurement wavelength: 280nm of

< quantification of glycosylhesperetin >

(1) Hesperidin content: the analysis was performed by HPLC, and the ratio of the peak area to the peak area of hesperidin (Fuji photo-pure chemical Co., ltd.) as a reagent of a standard substance at a given concentration was calculated.

(2) Alpha-glucosyl hesperidin content: analysis was performed by HPLC, and was calculated based on the ratio of the peak area to the peak area of the reagent hesperidin (Fuji film and Wako pure chemical industries, ltd.) of a standard substance at a given concentration, and the molecular weight ratio of alpha-glucosyl hesperidin to hesperidin.

(3) 7-O-beta-glucosyl hesperetin content: analysis was performed by HPLC, and was calculated based on the ratio of the peak area to the peak area of the reagent hesperidin (Fuji photo-pure chemical Co., ltd.) of a standard substance at a given concentration, and the molecular weight ratio of 7-O-beta-glucosyl hesperetin to hesperidin.

(4) Other glycosyl hesperetin content: analysis was performed by HPLC, and the ratio of the peak area to the peak area of hesperidin (sold by Fuji film and Wako pure chemical industries, ltd.) as a reagent of a standard substance at a given concentration, and the molecular weight ratio of other glycosyl hesperetin to hesperidin were calculated.

In a suitable embodiment, the glycosylhesperetin contained as an active ingredient of the lens hardness modifier of the present invention may be α -glycosylhesperidin including α -glycosylhesperidin. In this case, the suitable content of α -glucosyl hesperidin in glycosyl hesperetin is usually 60% by mass or more and less than 100% by mass, preferably 70% by mass or more and less than 100% by mass, more preferably 75% by mass or more and less than 100% by mass per unit dry solid matter. The upper limit of the content of α -glucosyl hesperidin in the glycosyl hesperetin contained as the active ingredient of the lens hardness modifier of the present invention is substantially less than 100% by mass as described above, and in a preferred embodiment, the content of α -glucosyl hesperidin in the glycosyl hesperetin is 99% by mass or less, more preferably 95% by mass or less, still more preferably 90% by mass or less, which can be provided industrially in relatively large amounts, at low cost and easily, from the viewpoint of providing the lens hardness modifier of the present invention at a lower cost. In a preferred embodiment, the lower limit of the content of α -glucosyl hesperidin in the glycosyl hesperetin contained as the active ingredient of the crystalline lens hardness regulator according to the present invention is preferably 60% by mass or more, more preferably 70% by mass or more, and still more preferably 75% by mass or more, for the same reason as the content of glycosyl hesperetin in the glycosyl hesperetin mixture.

The intake amount of the lens hardness adjuster of the present application is not particularly limited, and may be appropriately adjusted according to the intake frequency of the preparation, the state of the body of the user, and the like, and in a suitable embodiment, when all of glycosyl hesperetin as an active ingredient is regarded as hesperidin, the mass conversion (hereinafter, abbreviated as "conversion to hesperidin" in the present specification) is carried out, the amount may be usually 0.2 to 100mg/kg, preferably 0.4 to 80mg/kg, more preferably 0.6 to 40mg/kg, still more preferably 0.8 to 20mg/kg, and still more preferably 1 to 10mg/kg, in terms of hesperidin per day. That is, for example, in the case of ingestion by a person weighing 50kg, it may be generally in the range of 10 to 5000mg, preferably 20 to 4000mg, more preferably 30 to 2000mg, still more preferably 40 to 1000mg, still more preferably 50 to 500mg in terms of hesperidin per day. The number of times of ingestion may be several times. In addition, the period of the intake of the lens hardness regulator of the present application is not particularly limited, and may be taken in a single to several times, and in a suitable embodiment, it is desirable to take the regulator usually for 1 week or more, preferably for 2 weeks or more, more preferably for 4 weeks or more, still more preferably for 8 weeks or more, and still more preferably for 12 weeks or more. If the amount is less than the lower limit of the intake amount, the desired effect may be significantly reduced or not exhibited, while if the amount exceeds the upper limit of the intake amount, the effect corresponding to the amount to be administered may not be exhibited, and it is not preferable from the viewpoint of economy.

As described above, the lens hardness adjuster according to one embodiment of the present invention contains various glycosyl hesperetin as an active ingredient. As will be described in detail later, the effects of the lens hardening inhibition and/or lens softening are exhibited by a person by daily and continuous oral intake of a lens hardness regulator or the like containing glycosyl hesperetin as an active ingredient. In addition, in a suitable embodiment, the lens hardness regulator containing glycosyl hesperetin as an active ingredient can be used for preventing, alleviating and improving not only symptoms such as poor focal adjustment, myopia vision decrease and the like caused by aging and various diseases, but also eye fatigue, eye blur, eye pain, xerophthalmia, shoulder soreness, headache, neck, shoulder, wrist and back pain, fatigue, paralysis of hands and feet, dizziness and insomnia caused by poor focal adjustment, myopia vision decrease and the like, the functional food can be advantageously used as a supplement, a health food, a beauty food, a nutritional functional food, a health functional food, a specific health food, a special food, a quasi-drug, a pharmaceutical product, or the like, because of various symptoms such as increase in stress, decrease in activity, decrease in weight, decrease in muscle strength, decrease in bone density, decrease in vitality, decrease in cognitive function, increase in risk of falling, and the like, and various diseases such as cataract, glaucoma, retinal detachment, retinopathy, maculopathy, choroidal neovascularization, posterior scleral grape swelling, eye diseases such as eye diseases caused by aging, and the like. In a preferred embodiment, the lens hardness adjuster containing glycosyl hesperetin as an active ingredient may be suitably used in combination with other functional foods, health foods, beauty foods, nutritional functional foods, health functional foods, functional expression foods, specific health foods, quasi drugs, medicines, or foods and drinks.

In addition, as shown in experimental examples described later, in a certain suitable manner, the lens hardness modifier of the present invention can be suitably used for the prevention, alleviation and improvement of myopia vision deterioration, in particular, the prevention, alleviation and improvement of myopia vision deterioration with age. The near vision is a vision at a distance of about 30 to 40cm, and is preferably a near vision measured with refractive correction in which the distance vision of both eyes is 0.7 or more as a decimal vision. The prevention, alleviation and improvement of the decrease in myopia vision may include delay of decrease in myopia vision, decrease in the degree of decrease in myopia vision, or increase in myopia vision, as compared with the case where glycosyl hesperidin is not taken. In the case where the lens hardness adjuster of the present invention is used for prevention, alleviation and improvement of myopia vision deterioration, the subject to which it is administered is not particularly limited, and in a suitable embodiment, it may be a person whose average value of the near point distance under refractive correction is 15 to 45cm, more preferably 20 to 40cm, still more preferably 25 to 35cm, when the binocular distance vision is decimal vision of 0.7 or more. Here, the near point distance is the closest distance at which the subject can be seen in a focused state, and can be measured by a method shown in an experimental example described later, for example. On the other hand, there is no particular limitation on the age of the subject, and in a suitable embodiment, the subject is preferably an adult from the viewpoint of significantly observing a decrease in myopia with age, more preferably the subject may be 20 to 70 years old, preferably 30 to 60 years old, more preferably 40 to 50 years old, still more preferably 45 to 50 years old. However, it is needless to say that a person under 20 years old may be the administration subject. In recent years, it has been clarified that the symptoms of dysregulation and presbyopia can occur in children of lower ages, and in one embodiment, the lens hardness adjuster of the present invention can be suitably used for preventing, alleviating or improving the symptoms of dysregulation and presbyopia in such children of lower ages, for example, in people less than 20 years old.

In addition, in a preferred embodiment, if the lens hardness regulator containing glycosyl hesperetin is used in combination with 1 or 2 or more components such as other animal and plant substances, extracts thereof, compounds thereof, and the like having vision deterioration preventing, alleviating and improving effects, the lens hardening inhibitory effect and lens softening effect by glycosyl hesperetin are more effectively exerted, and at the same time, the above-mentioned prevention, alleviation, improvement of symptoms such as focal regulation failure such as presbyopia and myopia vision deterioration, and the above-mentioned prevention, alleviation and improvement of various diseases are more effectively exerted, which is preferable.

Examples of other animal and plant substances, extracts or compounds thereof having vision deterioration preventing, alleviating and improving effects include animal substances such as calculus bovis, margarita, concha Ostreae, agkistrodon halys, lumbricus epidermis, fel Ursi, cornu Saigae Tataricae, and cornu Cervi Pantotrichum, and extracts thereof; artichoke, setaria, fraxinus chinensis, america bean, herba Chenopodii, radix Rubiae, rehmanniae radix, autumn cornel, herba Solani Nigri, vitex agnus-castus fruit, medulla Tetrapanacis, brazilian blackberry fruit, herba Alii Fistulosi, resina Ferulae, nanfolia, thujoram, camellia sinensis, peruvian Huang Lajiao, herba Agrimoniae, rape, quercus suberectus, cone fruit, pimpinella, hamamelis, arnica, arristine, herba Pyrolae, herba Polygoni Cuspidati, italian celery, semen Ginkgo, japanese pyrolae, strawberry, bulbus Lilii, algae, herba Nepetae, narcissus, dillera, formica Fusca, cortex Meliae, acer, torilowii, hamamelis, herba Pyrolae, radix Curcumae, herba Solani Nigri, radix Angelicae sinensis, semen Castanae, radix Stephaniae Japonicae, radix Adinae, radix et rhizoma Kadsurae, radix Kadsurae, herba Hedyotidis Diffusae, herba Chelidonii herba Epimedii, fructus Rosae Davuricae, echinacea, perilla frutescens, herba Centipedae, radix Acanthopanacis Senticosi, flos Caraganae Sinicae, hercampure (by using Lauraria), ramulus Sambuci Williamsii, yerba mate (by using Lauraria), herba Avenae Fatuae, fructus Piperis, radix astragali, sugar palm, cortex Phellodendri, coptidis rhizoma, herba Violae, fenglong, herba Gynostemmatis, herba plantaginis, caragana round, fructus Hordei vulgaris, salicomia Herbacea, radix Panacis Quinquefolii, bulbus Lilii, herba Equiseti Aromatis (by using Latifolia), plumbum Preparatium, oregano, fructus Citri Tangerinae, cava (by using Lauraria), orchidaceae, fructus Zanthoxyli, fructus Cucurbitae, catuaba bark (by using Lauraria, caulis et folium Brassicae Junceae, radix Brassicae Junceae, fructus Ponciri Cynanchi Paniculatae, kazae, kazafimbriatae, semen Strychni, fructus Amomi rotundus, herba Zosterae Marinae, radix Platycodi, radix Glycyrrhizae, herba Hedyotideae, caulis Sargentodoxae, radix Et folium Gaultheriae Yunnanensis, radix Glaucae Pubescentis, radix Glaucae, radix Polygalae, and herba Saussae Fructus Cari Carvi, allium victorialis, semen Armeniacae amarum, fructus Citri Tangerinae, herba Sidae Rhombifoliae, folium Piperis Longi, radix Dictamni, caulis et folium Gaultheriae Yunnanensis, caulis Akebiae, radix Puerariae, fructus Gardeniae, cuminum celery, radix Sophorae Flavescentis, salvia officinalis, bulbus Lilii, juglandis, grapefruit, herba Oenanthes Javanicae, flos Caryophylli, semen Sinapis Albae, herba Schizonepetae, capsici fructus, semen Cassiae, herba Erodii seu Geranii, cowberry fruit, fructus Piperis, herba Andrographitis, herba Coriandri, sargassum, fructus Granati, sweet potato, zizyphi fructus, stigma croci Sativi, rhizoma Smilacis chinensis, fructus crataegi, fructus Zanthoxyli, fructus Citri Sarcodactylis, radix Angelicae Pubescentis Lantern pepper, purple perilla, winged bean, lithospermum, cinnamon bark, branches, root bark, spiraea, paeonia lactiflora, jasmine, paeonia lactiflora, ophiopogon japonicus, ginger, cimicifuga foetida, rheum palmatum, dongfengpi, white mustard, quinoa, chamomile, eaglewood, citrus tangutica, stenovia, licorice, sage, savory, nettle of different types, plantain, san johnsony, valerian, mustard, dandelion, elder, falcate, falcate knotweed herb, mandshurica, and the like horseradish, sleeka cinnamon bark, branch, root bark, cornflower, water celery, ligusticum wallichii, swertia, buckwheat, sorrel, rhubarb, radish, dahurian rhodobush, thyme, taiwan lily, polygonum, cardamom, davila ragosa (dawn), onion, japanese lily, tarragon, chicory, mountain radish, chive, willow leaf, clove, angustifolia, centella asiatica, onion (leyball), polygonum multiflorum, daisy, dill, hooked grass, ligularia, musk lily, hooked grass root, sweet tea, chilli, root of common angelica, fruit, peach kernel, cordate houttuynia, lotus, rosa roxburghii, bamboo joint, ginseng, eucommia ulmoides leaf, tomato, potentilla chinensis, folic acid, xia Baiju, jujube, wormwood, leek, elder, garlic, goldenrod, saw, wild chrysanthemum, mountain onion, basil, herba Ocimi, herba violae, radix et Gemma, radix scrophulariae, herba cistanches, and radix Angelicae sinensis, peppermint, lilium, lespedeza, clomazone, ginger, wild taro, parsley, patchouli, passion fruit, coix seed, vanilla, halvana pepper, brazil ginseng root, red pepper, nutgrass galingale rhizome, tribulus terrestris, pornogram, jalapeno, green pepper, cherokee rose, achyranthes, cypress, long pepper, false long pepper, sunflower, umbrellas, monoflower leeks, red lead, huang Ancai (Lavender's コ), black pepper (poncirus), areca, non-erysipelas, snakegourd fruit, fenugreek seed, fennel, bee bucket leaf, hyacinth bean, black cimicifuga rhizome, pomelo, luffa, wild chrysanthemum, henna, rutin, wind, peony, ephedra, marjoram, pine, japanese lilium, seed, horse chestnut seed, orange, root, bupleurum, duck's, green tea, fenugreek radix Angelicae Pubescentis, herba Pogostemonis, fructus Chaenomelis, echinacea purpurea, nemacystus Decipiens, willow, herba Senecionis Scandentis, rhizoma Dioscoreae, bulbus Lilii, herba Alii Fistulosi, fructus Citri Grandis, herba Caesalpiniae, herba Pogostemonis, fructus litchi seed, fructus Citri Reticulatae Chachiensis, fructus Foeniculi, herba Pogostemonis, fructus Foeniculi, and herba Pogostemonis lime, allium macrostemon, heracleum hemsleyanum, lavender, stachys sieboldii, lily, leek, bitter bamboo, raspberry, immature apple, jacquard, louis's wave, cotton bud sesame seed, rheum officinale, borage, lettuce, lemon grass, thyme, verbena, lemon balm, lemon carambola, lemon peach, fructus forsythiae, rose hip, rose bud, rosemary, rose red, roselle, laurel tree, tree pepper (ii コ), rose-red chrysanthemum, sappan wood, chive, horseradish, garden burnet, astragalus sinicus, persimmon leaf, licorice leaf, plants such as black soybean seed coat, black rice seed, radix et rhizoma Rhei peaches leaf, bulbus Lilii, radix Panacis Quinquefolii, herba Euphorbiae Humifusae, etc., or extracts thereof; extracts of seaweed such as gloiopeltis acutifolia, gloiopeltis horn, etc.; extracts of green coffee beans, sweet potato distillers grains, porous mushroom mycelia, agaricus mycelium, etc.; polyphenols such as resveratrol, quercetin, chlorogenic acid, anthocyanin, curcumin, kaempferol, epicatechols, flavonoids, etc.; carotenoids such as astaxanthin, beta-cryptoxanthin, lycopene, fucoxanthin, lutein, crocetin, retinol, retinal, retinoic acid, beta-carotene, pilocarpine such as pilocarpine hydrochloride, ephedrine, aspirin, sodium salicylate, insulin, epinephrine, acetylcholine, salicin, salicylic acid, choline salicylate, diflunisal, anthranilamide, mefenamic acid, diclofenac, sulindac, indomethacin, felbinac, etodolac, tolmetin, nabumetone, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, oxaprozin, loxoprofen, zatolprofen, ketorolac, piroxicam, ampiroxicam, meloxicam, lornoxicam, tenoxicam, celecoxib, valdecoxib, parecoxib sodium Tilapia hydrochloride, tenolidine hydrochloride, epidazole, rimofzone, azopyrazole, acetaminophen, phenylbutazone, oxyphenbutazone, ketophenylbutazone, feprazone, bupropion, antipyrine, analgin, isopropylantipyrine, glycine, theanine, GABA, sake yeast, diphenhydramine hydrochloride, zolpidem tartrate, triazolam, zopiclone, eszopiclone, etizolam bromatozolam, li Maza encapsulation hydrochloride, clomazone, flunitrazepam, esmolam, nitrazepam, quazepam, fluzepam hydrochloride, halo Shalun, ramelteon, suvorexant, mirtazapine, amitriptyline, mianserin, trazodone, risperidone, olanzapine, quetiapine, levopromazine, chlorpromazine, allicin, capsaicin, dihydrocapsaicin, shogaol, gingerol, zingiberene, piperine, sanchinin, sanshool amide, geraniol, allyl isothiocyanate, phenethyl isothiocyanate, myrosinin, sinigrin, glucoraphanin, equol, isoflavone, L-tyrosine, L-phenylalanine, L-tryptophan, 1,3, 5-trihydroxybenzene, 3, 4-dihydroxyphenylacetic acid, L-3, 4-dihydroxyphenylalanine, 4- (2-aminoethyl) benzene-1, 2-diphenol, norepinephrine, epinephrine, 5-hydroxytryptamine, caffeic acid, ifenprodil, alpha-lipoic acid, 4-hydroxychalcone, ergothione, resveratrol, carnosine, carnitine, norswine tricholine hydrobromide, sinapic acid, ferulic acid, cinnamic acid, tocopheryl nicotinate, alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-nicotinic acid alpha-tocotrienols, beta-tocotrienols, gamma-tocotrienols, delta-tocotrienols, nicotinamide, procyanidins, hydrolyzable tannins, catechol, chlorogenic acid, isochlorogenic acid, neochlorogenic acid, cryptochlorogenic acid, caffeoylquinic acid and other chlorogenic acids, procyanidins, leucocyanidin, matricarin, li Gan (alpha-tocopherols), procyanidin-oligomers, glucosyl rutin, glucosyl naringin, lutein, astaxanthin, delphinidin glucoside, berry extract, blueberry extract, cowberry extract, plum extract, vitamin A, vitamin B2, vitamin B6, vitamin B12, vitamin E, docosahexaenoic acid, eicosapentaenoic acid, beta-carotene, alpha-lipoic acid, lecithin, zinc, selenium, L-glutathione, N-acetyl-L-cysteine, lycopene, sesamin, zeaxanthin, taurine, lactobacillus, coenzyme Q10, green tea extract, ginkgo leaf extract, grape seed extract, pine bark extract, or derivatives thereof, etc.

The form of the lens hardness adjuster of the present invention is not particularly limited, but in some suitable manner, for example, it can be made: lozenge, liver oil pill, compound vitamin, mouth refrigerant, mouth fragrant tablet, oral/tube nutritional agent, oral medicine, etc., or solid, granule, powder, suspension, paste, jelly, capsule, liquid form, etc., or can be mixed with above composition. The method for preparing the above-described form and the method for adding the above-described form to the various compositions are not particularly limited, and for example, 1 or 2 or more known methods such as blending, kneading, mixing, adding, dissolving, impregnating, penetrating, dispersing, coating, spraying, and injecting can be suitably used in the step before the completion of the composition in the above-described form. The amount of glycosyl hesperetin to be incorporated into the preparation as an active ingredient of the lens hardness modifier of the present invention may be such that the desired effect is achieved.

As described above, the lens hardness adjuster according to the embodiment of the present invention containing glycosyl hesperetin as an active ingredient can suppress hardening of the lens, particularly hardening of the lens with age, and/or soften the temporarily hardened lens. Accordingly, the present invention also provides, in another aspect, a method for adjusting the hardness of a lens characterized by using glycosyl hesperetin as an active ingredient, more specifically, a method for inhibiting the hardening of a lens or a method for softening a lens. In these methods, the composition, production method, content, intake amount, combination of other components, and the like, which are suitable for the glycosyl hesperetin used as the active ingredient, are the same as those described for the hardness regulator for the crystalline lens. The method for adjusting the hardness of a crystalline lens according to one embodiment of the present invention, which is characterized by using glycosyl hesperetin as an active ingredient, is advantageously useful as a method for preventing, alleviating, and improving symptoms such as poor focal adjustment, myopia vision deterioration, etc. caused by aging and various diseases, and is also advantageously useful as a method for preventing, alleviating, and improving various diseases such as cataract, glaucoma, retinal detachment, retinopathy, maculopathy, choroidal neovascularization, posterior uveitis, and eye diseases such as falling down due to aging, eye fatigue, eye blur, eye pain, dry eye, shoulder pain, neck, shoulder, wrist, back pain, fatigue, paralysis of hands and feet, dizziness, insomnia, increase in pressure, decrease in activity, decrease in weight, decrease in muscle strength, decrease in bone density, decrease in cognitive function, increase in depression, etc. caused by aging, eye diseases such as posterior uveal swelling, and nerve channel.

The present invention will be described in more detail using the following experiments.

< experiment 1: effect of glycosyl hesperetin administration on sodium selenite-induced hardening of the rat lens

A test for measuring hardness of the lens was performed by administering a sample containing glycosyl hesperetin or a control sample to a rat, which had been induced to harden the lens by subcutaneous injection of sodium selenite, as a model animal.

< experiment 1-1: preparation of glycosyl hesperetin

Glycosyl hesperetin was prepared according to the method described in example 1 of WO2015/133483 pamphlet. Specifically, 4 parts by mass of a 1-equivalent aqueous sodium hydroxide solution was heated to 80℃and 1 part by mass of hesperidin and 7 parts by mass of dextrin (DE 20) were added thereto, and the mixture was stirred for 30 minutes to thereby dissolve the mixture and the mixture was allowed to react for 18 hours while maintaining the pH at 6.9 and 50℃with a cyclodextrin-glucan transferase derived from Geobacillus stearothermophilus (Geobacillus stearothermophilus) Tc-91 strain (independent administration product evaluation technique, base plate mechanism patent microorganism support No. FERM BP-11273) having 30 units per gram of dextrin. Then, after the enzyme remaining in the obtained enzyme reaction solution was heat-inactivated, 100 units of glucoamylase (trade name: about コ Seattle, manufactured by Nagase chemmex Co., ltd.) was added per gram of the solid content of the enzyme reaction solution, and the reaction was carried out for 5 hours while maintaining the pH at 5.0 and 55 ℃. The resulting enzyme reaction solution was heated to inactivate the remaining enzyme, filtered, and the filtrate was passed through a column packed with a porous synthetic adsorbent (trade name "Diaion HP-10", sold by Mitsubishi chemical Co., ltd.) using SV 2. Next, the column was washed with purified water, and then the concentration of the ethanol aqueous solution was gradually increased, and the solution was further passed through the column, to obtain a fraction containing α -glucosyl hesperidin, which was concentrated under reduced pressure and powdered to obtain a pale yellow glycosylhesperetin powder. The glycosyl hesperetin powder obtained in this example contained 80.0 mass% of α -glucosyl hesperidin, 12.3 mass% of hesperidin and 7.7 mass% of other components, and was equivalent in composition to the commercial glycosyl hesperetin (trade name "linn former hesperidin S", sold by the company ltd).

< experiment 1-2: preparation of test sample

A sample 1 was prepared by dissolving 200mg of the glycosylhesperetin powder obtained in experiment 1-1 in 10mL of phosphate buffered saline (PBS: 130mM sodium chloride, 3mM potassium chloride, 10mM disodium hydrogen phosphate, 2mM potassium dihydrogen phosphate, pH 7.4). As a control sample, PBS was used.

< experiments 1-3: glycosyl hesperetin short term administration test

SD male rats of 13 days of age were divided into test group 1: PBS injection and control sample dosing group, test group 2: PBS injection and tested sample 1 dosing group, test group 3: sodium selenite injection and control sample administration group, test group 4: the sodium selenite was injected and the test sample 1 was administered to the 4 groups, so that each group was 3. Test groups 2 and 4 were orally taken with 0.2mL (10 mL/kg body weight, equivalent to 200mg/kg body weight in terms of glycosylhesperetin) of the test sample obtained in experiment 1-2 and test groups 1 and 3 were orally taken with 0.2mL of PBS using a stomach tube feeding method once a day for 3 consecutive days. For test groups 3 and 4, after 4 hours of the first gastric feeding, sodium selenite (Fuji photo-pure chemical Co., ltd.) was subcutaneously injected at a concentration of 0.35mg/mL in an amount of 20. Mu. Mol/kg body weight to induce hardening of the lens. For test groups 1 and 2, PBS was subcutaneously injected in place of sodium selenite. The hardness of the lens of the 17-day-old rat was measured rapidly. The groups were identical in terms of feeding environment such as feed (trade name "CE-2", manufactured by Japanese CLAIR Co., ltd.), temperature (23.+ -. 5 ℃), humidity (50.+ -. 10%), illumination (12 hours in the bright period and 12 hours in the dark period).

< evaluation item and evaluation method >)

The evaluation items were the hardness of the lenses of the 17-day-old rats of each test group. The hardness of the lens was evaluated by using a compliance measuring device (softread HG1003-SL, manufactured by horiba motor, inc.). Specifically, immediately after euthanizing the rat, the lens was removed. The extracted lens was placed in a measuring table with its inner side facing downward, a flat indenter having a diameter of 12mm was aligned with the center of the lens, and then the lens was lowered in the vertical direction, and a pressure was applied to the lens at a press-in speed of 0.1 mm/sec. The load and the recess of the lens at this time were measured, and the load at which the lens was 15% recessed was used as an index of the hardness of the lens. The average and standard error of the load at which 15% of the recess was produced in the lens of each test group are shown in table 1.

< statistical resolution >

The measured values are expressed as mean.+ -. Standard Error (SE). SPSS software version 24 (from IBM corporation, japan) was used in statistical analysis, and after dispersion analysis using one-way analysis of variance (one-way ANOVA), a Tukey multiplex comparison assay was used. As a significance level (p-value), less than 0.05 (risk less than 5%) was judged as a significant difference.

TABLE 1

* : p < 0.05vs test group 3 (sodium selenite injection + control sample administration group)

As shown in table 1, in test group 1, the average value of the load (hereinafter, simply referred to as "load" unless otherwise noted) at which 15% of the concavity of the lens was generated as an index of the hardness of the lens was 4.0±0.2mN, whereas in test group 3, the average value of the load showed a significantly high value of 7.5±0.6mN, and therefore, it was confirmed that hardening of the lens was induced due to sodium selenite injection. In contrast, in test group 4, the average value of the load showed a significantly low value of 3.8±0.4mN, and thus it was shown that hardening of the crystalline lens induced by sodium selenite injection was significantly inhibited by administration of test sample 1 containing glycosyl hesperetin. No significant difference was found in the load of test group 2 compared to test group 1.

From the above results, it was confirmed that hardening of the lens induced by subcutaneous injection of sodium selenite was inhibited by ingestion of glycosyl hesperetin. The results illustrate that: glycosyl hesperetin has a lens hardening inhibition effect, and is useful as an active ingredient of a lens hardness regulator.

< experiment 2: effect of Low concentration of glycosyl hesperetin on hardening of rat crystalline lens induced by sodium selenite >

In experiment 1, in test group 4 in which glycosylhesperetin was continuously administered at an administration amount of 200mg/kg body weight every 1 day for 3 days, a lens hardening inhibition effect was found. Thus, since the inhibition of hardening of the crystalline lens by short-term administration of glycosyl hesperetin was found, a sample containing glycosyl hesperetin at a lower concentration than in experiment 1 was prepared, and whether or not the inhibition of hardening of the crystalline lens was obtained when the sample containing glycosyl hesperetin was administered at a smaller dose than in experiment 1 was examined.

< experiment 2-1: preparation of test sample

A product obtained by dissolving 200mg of glycosylhesperetin powder obtained in experiment 1-1 in 2000mL or 200mL of PBS was prepared as a test sample 2 and a test sample 3, respectively. On the other hand, as a control sample, PBS was used.

< experiment 2-2: glycosyl hesperetin short term dosing trial 2 >

SD male rats of 13 days of age were divided into test group 5: PBS injection and control sample dosing group, test group 6: sodium selenite injection and control sample dosing group, test group 7: sodium selenite was injected and tested in the test sample 2 dosing group, test group 8: the sodium selenite was injected and the test sample 3 was administered to these 4 groups, so that each group was 3. Test group 7 was orally taken with 0.2mL (10 mL/kg body weight, equivalent to 1mg/kg body weight in terms of glycosyl hesperetin) of test sample 2 obtained in experiment 2-1, and test group 8 was orally taken with 0.2mL (10 mL/kg body weight, equivalent to 10mg/kg body weight in terms of glycosyl hesperetin) of test sample 3 obtained in experiment 2-1, and test groups 5 and 6 were orally taken with 0.2mL of PBS, respectively, using a stomach tube feeding method once a day and 3 days. In test groups 6 to 8, sodium selenite was subcutaneously injected at a concentration of 0.35mg/mL to a body weight of 20. Mu. Mol/kg at 4 hours after the first gastric feeding, inducing hardening of the lens. In test group 5, PBS was subcutaneously injected in place of sodium selenite. The hardness of the lens of the 17-day-old rat was measured rapidly. The feeding environment of rats was the same as in experiment 1.

< evaluation item and evaluation method >)

The evaluation items were the hardness of the lenses of the 17-day-old rats of each test group. The hardness of the lens was measured in the same manner as described in experiments 1 to 3. Table 2 shows the average value and standard error of the load when 15% of the lens is depressed, as an index of the hardness of the lens caused by ingestion of each sample relative to the hardening of the lens during the feeding period.

< statistical resolution >

The measured values were expressed as mean.+ -. Standard Error (SE), and the statistical analysis was performed by the same method as described in experiments 1 to 3.

TABLE 2

* : p < 0.05vs test group 6 (sodium selenite injection + control sample administration group)

* *: p < 0.01vs test group 6 (sodium selenite injection + control sample administration group)

As shown in table 2, in test group 5, the average value of the load at which 15% of the concavity of the lens was generated as an index of the hardness of the lens was 2.6±0.3mN, whereas in test group 6, the average value of the load showed a significantly high value of 7.5±0.6mN, and therefore it was confirmed that hardening of the lens was induced due to sodium selenite injection. In contrast, in test group 7, the average value of the load showed 4.5±0.5mN, and in test group 8, the average value of the load showed a significantly lower value of 3.4±0.4mN than that of the control sample administration group (test group 6), and thus it was shown that hardening of the lens induced by sodium selenite injection was significantly suppressed by administration of test sample 2 or test sample 3 containing glycosyl hesperetin. The average value of the load measured in test groups 7 and 8 was the same as the average value of the load measured in test group 4 in which glycosyl hesperetin was administered at a dose of 200mg/kg body weight per day in experiments 1 to 3.

From the above results, it was found that even if the amount of glycosyl hesperetin administered was significantly smaller than that of test group 4 of experiment 1, such as 1mg/kg body weight per day (test group 7) or 10mg/kg body weight per day (test group 8), the hardening of the crystalline lens induced by subcutaneous injection of sodium selenite was effectively inhibited by the ingestion of glycosyl hesperetin. The results indicate that glycosyl hesperetin has an extremely excellent lens hardening inhibition effect and is useful as an active ingredient of a lens hardness regulator.

< experiment 3: effect of prolonged intake of glycosylhesperetin on hardening of the lens with age >

In the lens hardening model experiments of experiments 1 and 2, since the hardening inhibition effect of the lens by short-term administration of glycosyl hesperetin was confirmed, hardness of the lens after long-term feeding was measured while taking a test sample or a control sample containing glycosyl hesperetin as a natural age increase model experiment.

< experiment 3-1: preparation of each test sample

A product was prepared as a test sample 4 or 5 in which the glycosyl hesperetin powder obtained in experiment 1-1 was completely dissolved in tap water so that the concentration became 1% by mass or 2% by mass. Tap water was used as a control sample.

< experiment 3-2: glycosyl hesperetin long term administration test

C57BL/6JJ male mice at 9 weeks of age were divided into test group 9, which is a 16-week group of administration: control sample intake group, test group 10: test sample 4 intake group, test group 11: test sample 5 intake group, test group 12 as 28 week group: control sample intake group, test group 13: test sample 4 intake group, test group 14: the test sample 5 ingests 6 groups of 6 groups. The test sample 4 obtained in the experiment 3-1 was orally taken by the test groups 10 and 13, the test sample 5 obtained in the experiment 3-1 was orally taken by the test groups 11 and 14, and the control sample was orally taken by the test groups 9 and 12 by a free drinking method in which mice were able to drink water at any time and at random. For test groups 9 to 11 (16-week-old group), the lenses of mice of 25 weeks of age were taken, and for test groups 12 to 14 (28-week-old group), the lenses of mice of 37 weeks of age were taken, and their hardness was rapidly measured. The groups were identical in terms of feeding environment such as feed (trade name "CE-2", manufactured by Japanese CLAIR Co., ltd.), temperature (23.+ -. 5 ℃), humidity (50.+ -. 10%), illumination (12 hours in the bright period and 12 hours in the dark period).

< evaluation item and evaluation method >)

For the evaluation items, the hardness of the lenses of the mice 9 weeks old before each sample intake and the mice 25 weeks old and 37 weeks old in each sample intake group were measured, respectively. The hardness of the lens was measured in the same manner as described in experiments 1 to 3. The average value and standard error of the load when 15% of the lens was dented were obtained as an index of the hardness of the lens produced by ingestion of each sample relative to the hardening of the lens with age by long-term feeding, and are shown in table 3. In addition, the body weight, water intake and food intake of the mice tested were measured for each group daily from the start of the test to the time of lens extraction. The average body weight change of the 16-week group (test groups 9 to 11) was shown in fig. 1, the average cumulative value of the water intake was shown in fig. 2, the average cumulative value of the food intake was shown in fig. 3, the average body weight change of the 28-week group (test groups 12 to 14) was shown in fig. 4, the average cumulative value of the water intake was shown in fig. 5, and the average cumulative value of the food intake was shown in fig. 6.

< statistical resolution >

TABLE 3

* : p < 0.05vs9 weeks of age (before administration)

The average body weight, average water intake and average food intake of each group are shown in fig. 1 to 6. In the 16-week group, a difference in total water intake occurred, but it was judged that the experimental results described later were not affected.

As shown in table 3, the average value of the load at 15% of the lens dents was 10.0±1.1mN for the 9-week-old mice before the administration of the test sample, and the average value of the load was increased to 11.0±1.6mN for the lens of the control sample intake group (test group 9) at 25-week-old, which is an index of the hardness of the lens, and the hardening of the lens with age was confirmed. In contrast thereto, also at 25 weeks of age, the average value of the load for the lenses of test group 10 and test group 11 to which test sample 4 or test sample 5 was administered for 16 weeks was 8.9±0.7mN, 7.8±3.0mN, respectively, which was significantly smaller than the average value (11.0±1.6 mN) of the load for test group 9 in which hardening of the lens with age was confirmed. The results showed that hardening of the lens with age was suppressed in test group 10 and test group 11 in which test sample 4 or test sample 5 was administered for 16 weeks. Furthermore, surprisingly, the average value of the load for the lenses of test group 10 and test group 11 was also significantly smaller than the average value (10.0±1.1 mN) of the load measured for the 9-week-old mice before the administration of the test sample. The results indicate that administration of sample 4 or sample 5 containing glycosyl hesperetin not only suppresses hardening of the lens with age, but also softens the lens.

As shown in table 3, the average value of the load at which 15% of the lens was depressed was 10.0±1.1mN as an index of the hardness of the lens of the 9-week-old mouse before the administration of the test sample, and the average value of the load was 11.6±0.4mN for the lens of the control sample intake group (test group 12) at 37 weeks of age, and further hardening of the lens with age was confirmed as compared with that at 25 weeks of age. In contrast thereto, also at 37 weeks of age, the average value of the load for the lenses of test group 13 and test group 14 to which test sample 4 or test sample 5 was administered for 28 weeks was 7.3±0.8mN, 8.0±0.4mN, respectively, which was significantly smaller than the average value (11.6±0.4 mN) of the load for test group 12 in which hardening of the lens with age was confirmed. The results showed that hardening of the lens with age was suppressed in the test group 13 and the test group 14 to which the test sample 4 or the test sample 5 was administered for 28 weeks. Furthermore, surprisingly, the average value of the load for the lenses of test group 13 and test group 14 was also significantly smaller than the average value (10.0.+ -. 1.1 mN) of the load measured for the 9-week-old mice prior to the administration of the test sample. The results indicate that administration of sample 4 or sample 5 containing glycosyl hesperetin not only suppresses hardening of the lens with age, but also softens the lens.

As described above, it was confirmed that the ingestion of glycosyl hesperetin reduced the hardening of the lens with age. The results indicate that glycosyl hesperetin has a lens hardening inhibitory effect and is useful as an active ingredient of a lens hardness regulator. Furthermore, it was confirmed that ingestion of glycosyl hesperetin not only suppresses hardening of the lens with age, but also reduces the hardness of the lens as compared with the 9-week-old test sample. The results indicate that glycosyl hesperetin has a lens softening effect and is useful as an active ingredient of a lens hardness regulator.

< experiment 4: effect of long-term ingestion of glycosyl hesperetin on hardening of the lens with age 2 >

In experiment 3, since the effect of inhibiting hardening and softening of the lens by long-term administration of glycosyl hesperetin was confirmed, a sample containing glycosyl hesperetin at a lower concentration than in experiment 3 was prepared, a test sample or a control sample containing glycosyl hesperetin was taken into mice, and the hardness of the lens after a period shorter than in experiment 3 was measured.

< experiment 4-1: preparation of each test sample

A product was prepared as a test sample 6, which was completely dissolved in tap water so that the concentration of the glycosyl hesperetin powder obtained in experiment 1-1 became 0.1 mass%. Tap water was used as a control sample.

< experiment 4-2: glycosyl hesperetin long term administration test 2 >

C57BL/6JJ male mice at 9 weeks of age were divided into test group 15, which is a 10 week dosing group: control sample intake group, test group 16: test sample 6 intake group, test group 17 as 15 week dosing group: control sample intake group, test group 18: the test sample 6 ingests 4 groups of 6 groups. Test groups 16 and 18 were orally taken with the test sample 6 obtained in experiment 4-1 by the free drinking method in which mice were able to drink water at any time and control samples were orally taken with test groups 15 and 17. The lenses of the mice of 19 weeks of age were collected from test groups 15 and 16 (10-week-old group), and the lenses of the mice of 24 weeks of age were collected from test groups 17 and 18 (15-week-old group), and their hardness was rapidly measured. The breeding environment of mice was the same as that of experiment 3.

< evaluation item and evaluation method >)

For the evaluation items, the hardness of the lenses of the mice 9 weeks old before each sample intake and the mice 19 weeks old and 24 weeks old in each sample intake group were measured, respectively. The hardness of the lens was measured in the same manner as described in experiments 1 to 3. As an index of hardness of the lens produced by ingestion of each sample relative to hardening of the lens with age by long-term feeding, the average value and standard error of the load when 15% dishing was produced in the lens are shown in table 4. In addition, the body weight, water intake and food intake of the mice tested were measured for each group daily from the start of the test to the time of lens extraction. The average body weight change of each group of mice (test groups 15 and 16) taken for 10 weeks is shown in fig. 7, the average cumulative value of the water intake is shown in fig. 8, the average cumulative value of the food intake is shown in fig. 9, the average body weight change of each group of mice (test groups 17 and 18) taken for 15 weeks is shown in fig. 10, the average cumulative value of the water intake is shown in fig. 11, and the average cumulative value of the food intake is shown in fig. 12.

< statistical resolution >

The measured values were represented by mean.+ -. Standard Error (SE), and the statistical analysis was performed by the same method as described in experiment 3.

TABLE 4

The average body weight, average water intake and average food intake for each group are shown in fig. 7 to 12. In the 10-week dosing group, a difference in total water intake occurred, but it was judged that there was no effect on the average intake and average body weight, and no effect was exerted on the experimental results described later.

As shown in Table 4, for the 9-week-old mice before administration of the test sample, the average value of the load at which 15% of the concavity of the lens was generated was 10.0.+ -. 1.0mN as an index of the hardness of the lens, and for the lens of the control sample intake group (test group 15) at 19 weeks of age, the average value of the load was increased to 10.7.+ -. 1.3mN, suggesting hardening of the lens with age. In contrast thereto, also at 19 weeks of age, the average value of the load for the lens of test group 16 to which test sample 6 was administered for 10 weeks was 9.0.+ -. 0.7mN, which is smaller than the average value (10.7.+ -. 1.3 mN) of the load for test group 15 in which hardening of the lens with age was confirmed. The results indicate that hardening of the lens with age was inhibited in test group 16 where test sample 6 was administered for 10 weeks. Furthermore, it was surprising that the average value of this load for the lens of test group 16 was smaller than the average value (10.0.+ -. 1.0 mN) of this load measured for the 9-week-old mice prior to administration of the test sample. The results indicate that administration of sample 6 containing glycosyl hesperetin not only suppresses hardening of the lens with age, but also softens the lens.

As shown in table 4, the average value of the load when 15% of the dents were generated in the lens as an index of the hardness of the lens of the 9-week-old mice before the administration of the test sample was 10.0±1.0mN, and the average value of the load when the lens of the control sample intake group (test group 17) at 24 weeks of age was increased to 10.7±0.5mN, and the progress of hardening of the lens with age was confirmed. In contrast thereto, also at 24 weeks of age, the average value of the load for the lens of the test group 18 to which the test sample 6 was administered for 15 weeks was 7.6±1.3mN, which is significantly smaller than the average value (10.7±0.5 mN) of the load for the test group 17 to which hardening of the lens with age was confirmed. The results showed that hardening of the lens with age was inhibited in test group 18 to which test sample 6 was administered for 15 weeks. Furthermore, surprisingly, the average value of this load for the lens of test group 18 was significantly smaller than the average value (10.0.+ -. 1.0 mN) of this load measured for the 9-week-old mice prior to the administration of the test sample. The results indicate that the test sample 6 containing glycosyl hesperetin was continuously administered, thereby not only suppressing the hardening of the lens with age, but also softening the lens.

In addition to the reduction of hardening of the lens with age by taking 1 mass% or 2 mass% aqueous solution of glycosyl hesperetin in experiment 3, it was confirmed in experiment 4 that hardening of the lens with age was also reduced by taking 0.1 mass% aqueous solution of glycosyl hesperetin. The results demonstrate that glycosyl hesperetin has an excellent lens hardening inhibition effect and is extremely useful as an active ingredient of a lens hardness regulator. Further, in experiment 3, it was confirmed that not only the hardening of the lens with age was suppressed by the continuous intake of the aqueous solution of 1 mass% or 2 mass% of glycosyl hesperetin, but also the hardness of the lens was decreased as compared with the start of the experiment, and that not only the hardening of the lens with age was suppressed but also the hardness of the lens was decreased as compared with the start of the experiment by the continuous intake of the aqueous solution of 0.1 mass% of glycosyl hesperetin. These results indicate that glycosyl hesperetin has a lens softening effect and is useful as an active ingredient of a lens hardness regulator.

< experiment 5: effect of low dose of glycosyl hesperetin on hardness of crystalline lens

In experiments 3 and 4, the hardening inhibition effect and the lens softening effect of the lens caused by the long-term administration of glycosyl hesperetin were confirmed, and therefore, after making mice take up the test sample or the control sample containing glycosyl hesperetin in a lower amount than in experiments 3 and 4 in a shorter period than in experiment 4, the hardness of the lens was measured.

< experiment 5-1: preparation of test sample

A product was prepared as a test sample 7, which was completely dissolved in tap water so that the concentration of the glycosyl hesperetin powder obtained in experiment 1-1 became 0.15 mass%. Tap water was used as a control sample.

< experiment 5-2: low dose glycosyl hesperetin dosing assay >

C57BL/6JJ male mice at 9 weeks of age were divided into pre-dosing, test group 19: control sample dosing group, test group 20: the test sample 7 was administered to the 3 groups, so that each group was 3.

Test sample 7 obtained in experiment 5-1 was orally taken in an amount of 0.2mL (an amount of 10mL/kg body weight, equivalent to an amount of 10mg/kg body weight in terms of glycosyl hesperetin) by test group 20 once a day and 15 times during 19 days by a stomach tube feeding method, and 0.2mL of tap water was orally taken in test group 19. The pre-dose groups were immediately tested for hardness by picking the lens of the mice at 9 weeks of age and test groups 19 and 20 after 6 hours (11 weeks of age) of 15 th gastric tube feeding. The feeding environment of the mice was the same as that of experiment 3.

< evaluation items and evaluation methods >

The evaluation items were hardness of the lens of a 9-week-old mouse before sample intake and a 11-week-old mouse after each sample intake. The hardness of the lens was measured in the same manner as in experiment 1. As an index of the hardness of the lens produced by ingestion of each sample relative to the hardening of the lens during rearing, the average value and standard error of the load when 15% dishing was produced in the lens are shown in table 5.

< statistical analysis >

The measured values are expressed as mean.+ -. Standard Error (SE). In the statistical analysis, the group before sample intake and the group after sample intake were compared by Student t-test using SPSS software version 24 (sold by IBM corporation). As a significance level (p-value), less than 0.05 (risk less than 5%) was judged as a significant difference.

TABLE 5

* : group p < 0.05vs9 weeks old (pre-dose)

As shown in table 5, the average value of the load at which 15% of the lens dents were generated was 11.4±0.8mN as an index of the hardness of the lens of the 9-week-old mice before the administration of the test sample, and the average value of the load was increased to 11.7±0.7mN for the lens of the control sample intake group (test group 19) at 11 weeks of age, confirming the progress of hardening of the lens with age. In contrast, at 11 weeks of age, the average value of the load on the lens of the test sample 7 intake group (test group 20) was 9.0.+ -. 0.3mN, which is smaller than the average value of the load (11.7.+ -. 0.7 mN) on the control sample administration group (test group 19). This result shows that hardening of the lens with age is suppressed in the test group 20 having ingested the test sample 7. Furthermore, surprisingly, the average value of this load for the lens of test group 20 was significantly smaller than the average value (11.4.+ -. 0.8 mN) of this load measured for the 9-week-old mice prior to administration of the test sample. The results showed that, by continuously administering the test specimen 7, not only hardening of the lens with age was suppressed, but also softening of the lens was also suppressed.

In experiment 5, it was confirmed that hardening of the lens with age was also inhibited by a short-term continuous intake of 0.15 mass% aqueous solution of glycosylhesperetin. The results indicate that glycosyl hesperetin has a lens hardening inhibitory effect and is useful as an active ingredient of a lens hardness regulator. Further, it was confirmed that continuous intake of 0.15 mass% aqueous solution of glycosyl hesperetin not only suppresses hardening of the lens with age, but also reduces the hardness of the lens as compared with the time of starting the test. These results indicate that glycosyl hesperetin has a lens softening effect and is useful as an active ingredient of a lens hardness regulator.

< experiment 6: long-term intake of glycosyl hesperetin has effect on myopia

In experiments 1 to 5, the effect of glycosyl hesperetin on myopia of a person was examined by measuring myopia after a long-term intake of glycosyl hesperetin, since the effect of glycosyl hesperetin on lens hardening inhibition and lens softening was confirmed.

< experiment 6-1: selection of the testee >

To select the subject, the near-point distance was measured for 51 healthy adults (31 to 61 years) as candidates. The near-point distance is one of the indicators of presbyopia, and a near-point distance measuring instrument is manufactured and used for measuring. Specifically, the subject is kept calm in the environment without looking at the smartphone or PC display, for example, 5 minutes before measurement, in a sitting state, in a refractive correction (in a state where the glasses are used by the person using the glasses). In the measurement of the near-point distance, after the forehead of the subject is brought into contact with the forehead fixed plate of the near-point distance measuring instrument, the movable plate to which the news report is attached is gradually moved away from the forehead fixed plate in a direction parallel to the floor by the subject's own hand, and the movable plate is stopped at the point (near point) at which the text of the news report attached to the movable plate is focused (focused), and the distance from the forehead fixed plate to the movable plate is measured by the measurer using a ruler. The value obtained by adding the thickness of the forehead fixing plate to the measured value is set as the near point distance. The near point distance was measured 3 times, and 32 persons (age 40 to 61 years) whose average value of the near point distance under refractive correction was 25 to 35cm as an index of initial presbyopia were classified into two groups so as to equalize near vision, sex and age described later.

In the near vision, after the subject was allowed to stand still in the environment without looking at a smartphone, a PC display, or the like in 5 minutes before measurement, in a sitting posture, under refractive correction, a near vision card with 40cm string, sold by TMI corporation, C & E, was used, and the measurement was performed with both eyes under refractive correction with a binocular presbyopia of 0.7 or more. In detail, in the upright state, a card displaying a optotype symbol such as Langmuir ring is provided at the same height as the height of the eyes of the subject, so that a 40cm rope connected to the card is not loosened, and the optotype symbol is answered in a state where the distance between the eyes and the card is maintained. The measurement is continued using smaller optotypes until the subject hesitates or fails to recognize the optotype. The average value of 32 subjects with myopia vision is 0.12, which ranges from-0.15 to 0.65. Here, the description of myopia vision uses a log MAR vision that can be numerically processed.

< experiment 6-2: preparation of each test sample

A test sample 8 (mass: 755mg/1 tablet) in the form of a tablet composed of the composition shown in Table 6 below and a control sample (mass: 758mg/1 tablet) having the same appearance and flavor were prepared as glycosyl hesperidin ("Linyuan hesperidin S", sold by Lingyo Co., ltd.) by a conventional method.

TABLE 6

< experiment 6-3: long-term ingestion of glycosyl hesperetin has an effect on myopia

The test person is allowed to take the test sample 8 or the control sample every two pieces a day and continuously for 3 months in an arbitrary time zone without knowing which of the test sample 8 and the control sample is taken. The myopia vision was measured in the same manner as in experiment 6-1, and was performed before the start of intake and after 1, 2, and 3 months after the start of intake. The test was designed as a randomized placebo controlled double-blind test. Table 7 and fig. 13 and 14 show the results of analysis of the amounts of change in myopia at the reference point before the start of intake, for subjects in the second half of the ages 40 and 40, in which the decrease in myopia with age was most significantly observed in general.

< statistical resolution >

The measured values are expressed as mean.+ -. Standard Error (SE). For the statistical analysis, IBM SPSS Statistics (sold by IBM corporation, japan) was used, and the statistical treatment was performed using the mann-whitney U test at each measurement point. As a significance level (p-value), less than 0.05 (risk less than 5%) was judged as a significant difference.

TABLE 7

* : control sample intake group with p < 0.05vs

* *: control sample intake group with p < 0.01vs

As shown in table 7, among subjects aged 40 years (40 to 49 years, n=17), the average value of the amounts of change in myopia of subjects (43 to 49 years, n=9) who ingested the control sample was 0.05±0.03, 0.01±0.04, and 0.02±0.04, respectively, after 1 month, 2 months, and 3 months from the start of sample ingestion, whereas the average value of the amounts of change in myopia of subjects (40 to 49 years, n=8) who ingested the test sample 8 was-0.04±0.02, and-0.06±0.02, respectively, after 1 month, 2 months, and 3 months from the start of sample ingestion, and conversely, the tendency of slow improvement in myopia was found. In particular, after 1 month and 3 months from the start of sample intake, a significant decrease in the amount of change in myopia vision was found in the subject who took the test sample 8, as compared with the subject who took the control sample. The results showed that in the subject 40 years old who ingested the test specimen 8, the decrease in myopia vision was significantly suppressed, and furthermore, surprisingly, not only the decrease in myopia vision was suppressed, but also myopia vision was improved. Further, surprisingly, when the subject was half of the last 40 years old (46 to 49 years old, n=10), the average value of the amounts of change in myopia of the subjects (46 to 49 years old, n=5) who took the control sample was 0.12±0.01, 0.10±0.02 and 0.10±0.02 after 1 month, 2 months and 3 months, respectively, after the start of sample intake, and the average value of the amounts of change in myopia of the subjects (46 to 49 years old, n=5) who took the test sample 8 was found to be significantly lower than the whole subject of 40 years old, whereas the average value of the amounts of change in myopia of the subjects (46 to 49 years old, n=5) who took the test sample 8 was found to be significantly lower in amounts of change in myopia, that is, the tendency of improvement in myopia, after 1 month, 2 months and 3 months, respectively, after the start of sample intake was found to be-0.05±0.02, -0.06±0.02 and-0.07±0.03. The results indicate that in the latter half of the age of 40, in which test sample 8 was taken, the decrease in myopia vision was suppressed, and that the myopia vision was significantly improved. The above results indicate that the reduction of myopia vision with age is suppressed and myopia vision is improved by long-term oral ingestion of glycosylhesperetin. The results indicate that glycosyl hesperetin has an effect of preventing or improving myopia and vision deterioration and focal spot dysregulation due to aging, and is extremely useful as an active ingredient of a crystalline lens hardness regulator.

The present invention will be specifically described below based on examples, but the present invention is not limited to these examples.

Example 1

Lens hardness modifier in powder form

A commercially available powder containing alpha-glucosyl hesperidin (trade name "Linyuan hesperidin S", sold by Linogen Co., ltd.) was used as a lens hardness regulator. The product has a lens softening effect or a lens hardening inhibiting effect, and can be added to various beverages such as water, tea, black tea, coffee, and other foods and beverages, thereby providing a lens hardness regulator which is orally taken in daily life and has excellent storage stability and thermal stability.

Example 2

Lens hardness modifier in tablet form

1 part by mass of a powder containing glycosyl hesperetin (82 parts by mass of α -glycosyl hesperidin, 1 part by mass of hesperidin, 8 parts by mass of 7-O- β -glycosyl hesperetin, 9% by mass of other components) (manufactured by the company, lin origin), 19 parts by mass of a powder containing α, α -trehalose dihydrate crystals (registered trademark "TREHA", sold by the company, lin origin), 0.1 part by mass of lutein, and 0.1 part by mass of astaxanthin were uniformly mixed and tableted according to a conventional method to obtain a tablet form of a tablet of 250 mg. The product has excellent lens softening action and lens hardening inhibition action, and can alleviate or improve symptoms of patients suffering from presbyopia, people suffering from focal regulation and myopia and vision deterioration and people worrying about presbyopia usually take glycosyl hesperetin which is equivalent to 10-5000 mg in terms of hesperidin every 1 day as a standard for adults, thereby effectively improving, delaying or preventing the onset of the symptoms.

Example 3

Lens hardness regulator in form of cooling drink

In 5000 parts by mass of water, 200 parts by mass of granulated sugar, 100 parts by mass of powder containing alpha, alpha-trehalose dihydrate crystals (registered trademark "TREHA", sold by Proprietary, co., ltd.), 6 parts by mass of citric acid, 6 parts by mass of sodium chloride, 0.2 part by mass of potassium chloride, 0.05 part by mass of calcium lactate, 0.01 part by mass of magnesium chloride, 5 parts by mass of alpha-glucosyl hesperidin crystal powder (purity 99% by mass or more, manufactured by Proprietary, co., ltd.) and 0.1 part by mass of powder containing anhydrous crystals of ascorbic acid 2-glucoside (registered trademark "Ascofresh", sold by Proprietary, co., ltd.) were uniformly dissolved to obtain a crystalline hardness regulator in the form of a cooling drink. The product has effects of softening and inhibiting lens hardening, and can be used for improving, relieving, and preventing focal dysregulation such as presbyopia and myopia, and reducing myopia and vision.

Example 4

Lens hardness modifier in hard candy form

10 parts by mass of a powder containing an α, α -trehalose dihydrate crystal (registered trademark "TREHA", sold by Proprietary corporation) and 20 parts by mass of water were concentrated under reduced pressure at 155 ℃ until the water content became about 2% or less, then cooled to 120 ℃, and 0.5 part by mass of an anhydrous crystalline powder of ascorbic acid 2-glucoside (registered trademark "Ascofresh", sold by Proprietary corporation) and 0.5 part by mass of a powder containing α -glucosyl hesperidin (trade name "Lin S", sold by Proprietary corporation), 0.01 part by mass of lutein, 0.01 part by mass of anthocyanin and an appropriate amount of lemon flavor were mixed thereinto, and then molded and packaged according to a conventional method to obtain a lens hardness regulator in a hard candy form. The product has effects of softening and inhibiting lens hardening, and is useful as a lens hardness regulator for improving, relieving, and preventing focal dysregulation such as presbyopia and myopia vision deterioration caused by aging and various diseases, and having good flavor and taste.

Example 5

Lens hardness modifier in chewing gum form

3 parts by mass of a gum base was melted by heating until it became soft, 6 parts by mass of α, α -trehalose (registered trademark "TREHA", sold by Proprietary corporation) and 1 part by mass of a powder containing glycosyl hesperidin (82% by mass of α -glucosyl hesperidin, 1% by mass of hesperidin, 8% by mass of 7-O- β -glucosyl hesperetin, 9% by mass of other components) (preparation of Proprietary corporation) were added, and further, 0.1 part by mass of a berry extract, a proper amount of coloring material and a proper amount of flavoring material were mixed, kneaded by a conventional method, molded, and packaged to obtain a chewing gum containing α -glucosyl hesperidin. The product has effects of softening and inhibiting lens hardening, and is useful as a lens hardness regulator for improving, relieving, and preventing focal dysregulation such as presbyopia and myopia vision deterioration caused by aging and various diseases, and having good flavor and texture.

Example 6

Lens hardness modifier in the form of a transoral nutritional agent

A complex was prepared comprising 30 parts by mass of maltose (trade name "maltose PH", sold by Proprietary), 3 parts by mass of sodium glutamate, 2 parts by mass of glycine, 2 parts by mass of sodium chloride, 0.3 part by mass of magnesium carbonate, 1 part by mass of calcium lactate, 5 parts by mass of alpha-glucosyl hesperidin crystal powder (purity 99% or more, product of Proprietary, corp.), 0.02 part by mass of vitamin A, 0.02 part by mass of vitamin B and 0.02 part by mass of vitamin B12. The complex was packed into laminated aluminum bags at 30g each, and heat-sealed to prepare a lens hardness adjuster in the form of a tube-through oral nutrient. The product has a lens softening effect or a lens hardening inhibiting effect, is dissolved in about 250 to 500mL of sterilized water, and can be used as a lens hardness regulator by tube or mouth, and is advantageously used as a liquid for improving, alleviating and preventing focal dysregulation such as presbyopia and myopia vision deterioration caused by aging and various diseases.

Example 7

Lens hardness modifier in capsule form

10 parts by mass of calcium acetate 1 water salt, 50 parts by mass of L-magnesium lactate 3 water salt, 57 parts by mass of maltose, 20 parts by mass of powder containing alpha-glucosyl hesperidin (trade name "linn hesperidin S", sold by Proprietary, co., ltd.) and 12 parts by mass of gamma-cyclodextrin clathrate containing 20% vitamin E were uniformly mixed with 1 part by mass of blueberry extract powder, and after granulating by a granulating machine, gelatin capsules were enclosed according to a conventional method to obtain a capsule-form lens hardness regulator containing 150mg of content per 1 capsule. The product has effects of softening and inhibiting lens hardening, and can be used as liquid for improving, relieving, and preventing focal dysregulation such as presbyopia and myopia vision deterioration due to aging and various diseases.

Example 8

Lens hardness modifier in capsule form

10 parts by mass of calcium acetate 1 water salt, 50 parts by mass of L-magnesium lactate 3 water salt, 57 parts by mass of maltose, 20 parts by mass of powder containing glycosyl hesperetin (82 parts by mass of alpha-glucosyl hesperidin, 1 part by mass of hesperidin, 8 parts by mass of 7-O-beta-glucosyl hesperetin, 9% by mass of other components) (manufactured by Corp. Linne products), 10 parts by mass of gamma-cyclodextrin inclusion compound containing 20% vitamin A, 0.5 part by mass of gamma-cyclodextrin inclusion compound containing 20% DHA, 0.5 part by mass of gamma-cyclodextrin inclusion compound containing 20% EPA, 0.5 part by mass of gamma-cyclodextrin inclusion compound containing 20% beta-carotene and 0.5 part by mass of gamma-cyclodextrin inclusion compound containing 20% alpha-lipoic acid were uniformly mixed, and after granulating by a granulation molding machine, gelatin capsules were encapsulated according to a conventional method to obtain capsule form crystalline hardness regulator containing 150mg of content per 1 capsule. The product has effects of softening and inhibiting lens hardening, and can be used as liquid for improving, relieving, and preventing focal dysregulation such as presbyopia and myopia vision deterioration due to aging and various diseases.

Example 9

Lens hardness modifier in Soft Capsule form

After 10 parts by mass of an alpha-glucosyl hesperidin crystalline powder (purity: 99% by mass or more, manufactured by Linne corporation), 10 parts by mass of a blueberry fruit extract, 2 parts by mass of a blackcurrant extract, 1 part by mass of delphinidin glucoside, 2 parts by mass of a beta-carotene 30% suspension, 0.1 part by mass of vitamin a, 0.1 part by mass of vitamin E, 0.1 part by mass of astaxanthin, 0.1 part by mass of lutein, 5 parts by mass of glycerin fatty acid ester, 20 parts by mass of soybean lecithin, and 65 parts by mass of safflower oil were uniformly mixed, and then coated with a soft capsule coating film containing gelatin and glycerin according to a conventional method, to obtain a crystalline lens hardness regulator in the form of a soft capsule containing 350mg of contents per 1 capsule. The product has effects of softening and inhibiting lens hardening, and can be used as liquid for improving, relieving, and preventing focal dysregulation such as presbyopia and myopia vision deterioration due to aging and various diseases.

Example 10

Lens hardness modifier in tablet form

29 parts by mass of a powder containing α -glucosyl hesperidin (registered trademark "lin" S ", sold by the company of the origin of the forest) and 70 parts by mass of maltose (registered trademark" SUNMALT ", sold by the company of the origin of the forest), and 1 part by mass of sucrose stearate, 0.1 part by mass of astaxanthin, 0.1 part by mass of green tea extract, 0.1 part by mass of ginkgo leaf extract, and 0.1 part by mass of grape seed extract were each uniformly mixed, and then tableted by a conventional method to obtain a lens hardness regulator in the form of a tablet. The product has excellent effect of adjusting hardness of crystalline lens, and thus has effects of improving, relieving, and preventing focal adjustment failure such as presbyopia and myopia vision deterioration due to aging and various diseases, and is also useful as health food.

Example 11

Lens hardness modifier in powder form

10 parts by mass of a powder containing glycosyl hesperetin (82 parts by mass of α -glycosyl hesperidin, 1 part by mass of hesperidin, 8 parts by mass of 7-O- β -glycosyl hesperetin, 9% by mass of other components) (manufactured by the company of the raw materials of the forest), 3 parts by mass of sucrose, 1 part by mass of maltitol, and 15 parts by mass of water-soluble dietary fiber (registered trademark "fibriyxa", sold by the company of the forest) were stirred and mixed, and 5g of each powder was accommodated in a rod-shaped light-shielding and moisture-proof packaging container, to obtain a crystalline lens hardness regulator in the form of powder. The product has effects of softening or inhibiting lens hardening, and can be daily taken orally by adding 1 to 3 bags of the product to various beverages such as water, tea, black tea, coffee, and other foods and beverages every day. The product has excellent effect of adjusting hardness of crystalline lens, and thus has effects of improving, relieving, and preventing focal adjustment failure such as presbyopia and myopia vision deterioration due to aging and various diseases, and is also useful as health food.

Example 12

Lens hardness modifier in tablet form

After 10 parts by mass of L-ascorbic acid, 19 parts by mass of alpha-glucosyl hesperidin crystal powder (purity: 99% by mass or more, manufactured by Linne corporation), 70 parts by mass of maltose (registered trademark "SUNMALT", sold by Linne corporation), 1 part by mass of sucrose stearate, 0.01 part by mass of zinc, 0.01 part by mass of selenium and 0.01 part by mass of L-glutathione were mixed uniformly, they were tableted by a conventional method to obtain a tablet-form lens hardness regulator. The product has a lens softening effect or a lens hardening inhibiting effect, and is useful as a lens hardness regulator having excellent flavor and texture. The product has excellent effect of adjusting hardness of crystalline lens, and thus has effects of improving, relieving, and preventing focal adjustment failure such as presbyopia and myopia vision deterioration due to aging and various diseases, and is also useful as health food.

Example 13

Lens hardness modifier in the form of "chewing gum

150 parts by mass of a commercially available syrup containing α -maltosyl trehalose (registered trademark "HALLODEX", sold by Proprietary corporation) was heated under reduced pressure, concentrated to a moisture content of 15% by mass, the product obtained by dissolving 13 parts by mass of gelatin in 18 parts by mass of water was uniformly mixed with 2 parts by mass of powder containing α -glucosyl hesperidin (trade name "linn former hesperidin S", sold by the company of linn), 2 parts by mass of citric acid, 0.1 part by mass of anhydrous crystalline powder of ascorbic acid 2-glucoside (registered trade name "Ascofresh", sold by the company of linn), 0.1 part by mass of glucosyl rutin and 0.1 part by mass of sodium chloride, and an appropriate amount of coloring material and flavoring agent according to a conventional method, and then molded and packaged to obtain a crystalline lens hardness regulator in the form of chewing gum containing α -glucosyl hesperidin. The product has a lens softening effect or a lens hardening inhibiting effect, and is useful as a lens hardness regulator having excellent flavor and texture. The product has excellent effect of adjusting hardness of crystalline lens, and thus has effects of improving, relieving, and preventing focal adjustment failure such as presbyopia and myopia vision deterioration due to aging and various diseases, and is also useful as health food.

Example 14

Lens hardness modifier in supplement form

1 part by mass of a powder containing glycosyl hesperetin (82 parts by mass of α -glycosyl hesperidin, 1 part by mass of hesperidin, 8 parts by mass of 7-O- β -glycosyl hesperetin, 9% by mass of other components) (manufactured by the company "fibriyxa", sold by the company "wood origin"), 50 parts by mass of a water-soluble dietary fiber (registered trademark), 10 parts by mass of a powder containing α, α -trehalose dihydrate crystals (registered trademark "TREHA", sold by the company "wood origin"), 0.1 part by mass of lycopene, 0.1 part by mass of sesamin, 0.1 part by mass of zeaxanthin, and 0.1 part by mass of taurine were uniformly mixed, and each 3g of the mixture was filled in a rod-shaped paper container coated with aluminum foil on the inner surface, to obtain a crystalline hardness regulator in the form of a supplement. The product has effects of softening and inhibiting lens hardening, and is useful as a lens hardness regulator with good flavor and taste. The product has excellent effect of adjusting hardness of crystalline lens, and thus has effects of improving, relieving, and preventing focal adjustment failure such as presbyopia and myopia vision deterioration due to aging and various diseases, and is also useful as health food.

Example 15

Lens hardness modifier in yoghurt form

40 parts by mass of alpha-glucosyl hesperidin crystal powder (purity: 99 mass% or more, manufactured by Linne corporation) 800 parts by mass of skim milk powder, and 4000 parts by mass of purified water were mixed to prepare a raw material (yogurt mix) for fermented milk, which was heat-sterilized at 95℃for 10 minutes, and then cooled to 45 ℃. Then, 100g of the mixed starter was inoculated, and the mixture was fermented in a jar at 47℃for 5 hours, and then cooled to 8℃or lower, to obtain a yogurt-form lens hardness regulator. The product exhibits a lens softening effect or a lens hardening suppressing effect, and is useful as a lens hardness regulator having excellent flavor and taste, and can be used for alleviating or improving symptoms of patients suffering from presbyopia, persons suffering from focal adjustment discomfort due to aging, or persons suffering from presbyopia by taking 100 to 500g daily every 1 day, usually by adults, and effectively delaying or preventing the onset of the disease. The product has excellent effect of adjusting hardness of crystalline lens, and thus has effects of improving, relieving, and preventing focal adjustment failure such as presbyopia and myopia vision deterioration due to aging and various diseases, and is also useful as health food.

Example 16

Lens hardness modifier in powder form

10 parts by mass of a powder containing α -glucosyl hesperidin (registered trademark "hesperidin S", sold by the company, ltd.) and 9 parts by mass of a powder containing α, α -trehalose dihydrate crystals (registered trademark "TREHA", sold by the company, ltd.) and 30 parts by mass of fructooligosaccharides (registered trademark "fructo-Oligo", sold by the company, ltd.) and 0.1 part by mass of a powder containing anhydrous crystals of ascorbic acid 2-glucoside (registered trademark "Ascofresh", sold by the company, ltd.) and 0.1 part by mass of lutein and 10.1 parts by mass of coenzyme Q were mixed with stirring, and each 5g of the mixture was contained in a rod-shaped light-shielding and moisture-proof packaging container, to obtain a crystalline hardness regulator in the form of powder. The product has effects of softening and inhibiting lens hardening, and can be used for improving, relieving, and preventing focal regulation failure such as presbyopia and myopia vision deterioration due to aging and various diseases, and can be added into various beverages such as water, tea, black tea, coffee, and other foods and beverages 1-2 bags per day for daily oral intake.

Example 17

Lens hardness modifier in Mixed sweetener form

100 parts by mass of isomerized liquid sugar, 1 part by mass of powder containing alpha, alpha-trehalose dihydrate crystals (registered trademark "TREHA", sold by Proprietary corporation), 1 part by mass of fructo-oligosaccharide (registered trademark "galacto-Oligo", sold by Proprietary corporation), and 2 parts by mass of powder containing glycosyl hesperetin (82 parts by mass of alpha-glucosyl hesperidin, 1 part by mass of hesperidin, 8 parts by mass of 7-O-beta-glucosyl hesperetin, 9% by mass of other components) (preparation of Proprietary corporation) were heated at 80℃for 30 minutes to obtain a crystalline hardness regulator in the form of a mixed sweetener. The product has good flavor and taste, and is useful as a liquid mixed sweetener having excellent effects of easily adjusting hardness of crystalline lens for heating and cooking various foods and beverages, improving, alleviating, and preventing focal adjustment failure such as presbyopia and myopia vision deterioration due to aging and various diseases.

Example 18

Lens hardness modifier in the form of a health aid beverage

The crystalline lens hardness adjuster in the form of a health-aid beverage was prepared by mixing and dissolving 40 parts by mass of isomerized sugar, 2 parts by mass of maltitol, 10 parts by mass of black vinegar, 5 parts by mass of cider vinegar, 2 parts by mass of citric acid, 2 parts by mass of malic acid, 2 parts by mass of concentrated apple juice, and 3 parts by mass of alpha-glucosyl hesperidin crystal powder (purity 99% or more, manufactured by Linne corporation). The product has good flavor and taste, and is useful as a crystalline hardness regulator having effects of improving, alleviating, and preventing focal regulation failure such as presbyopia and myopia vision deterioration caused by aging and various diseases.

Industrial applicability

As described above, the present invention relates to a lens hardness adjuster containing glycosyl hesperetin as an active ingredient, based on the unique insight that glycosyl hesperetin exerts a remarkable lens hardening inhibition effect and the like. Furthermore, based on the unique insight that glycosyl hesperetin exerts a remarkable softening action of the crystalline lens, the present invention relates to a crystalline lens hardness regulator containing glycosyl hesperetin as an active ingredient. The hardness regulator for a crystalline lens of the present invention is intended to be used by normal persons and patients frequently, and thus to have a maintenance or restoration effect of the hardness of the crystalline lens. In particular, the lens hardness adjuster of the present invention can be used as a lens hardness inhibitor or a lens softener, and is expected to prevent, alleviate and improve focal dysregulation such as presbyopia and deterioration of myopia vision due to aging and various diseases by being applied to a person who is concerned about hardening of the lens and a person who has developed hardening of the lens.

Description of the reference numerals

In the context of figure 1 of the drawings,

o: test group 9 (control sample intake group)

And (2) the following steps: test group 10 (test sample 4 uptake group)

■ : test group 11 (test sample 5 uptake group)

In the view of figure 2,

o: test group 9 (control sample intake group)

And (2) the following steps: test group 10 (test sample 4 uptake group)

■ : test group 11 (test sample 5 uptake group)

In the view of figure 3 of the drawings,

o: test group 9 (control sample intake group)

And (2) the following steps: test group 10 (test sample 4 uptake group)

■ : test group 11 (test sample 5 uptake group)

In the view of figure 4 of the drawings,

o: test group 12 (control sample intake group)

And (2) the following steps: test group 13 (sample to be tested 4 uptake group)

■ : test group 14 (test sample 5 uptake group)

In the view of figure 5 of the drawings,

o: test group 12 (control sample intake group)

And (2) the following steps: test group 13 (sample to be tested 4 uptake group)

■ : test group 14 (test sample 5 uptake group)

In the view of figure 6 of the drawings,

o: test group 12 (control sample intake group)

And (2) the following steps: test group 13 (sample to be tested 4 uptake group)

■ : test group 14 (test sample 5 uptake group)

In the view of figure 7 of the drawings,

o: test group 15 (control sample intake group)

■ : test group 16 (test sample 6 uptake group)

In the view of figure 8 of the drawings,

o: test group 15 (control sample intake group)

■ : test group 16 (test sample 6 uptake group)

In the view of figure 9 of the drawings,

o: test group 15 (control sample intake group)

■ : test group 16 (test sample 6 uptake group)

In the view of figure 10 of the drawings,

o: test group 17 (control sample intake group)

■ : test group 18 (test sample 6 uptake group)

In the view of figure 11 of the drawings,

o: test group 17 (control sample intake group)

■ : test group 18 (test sample 6 uptake group)

In the view of figure 12 of the drawings,

o: test group 17 (control sample intake group)

■ : test group 18 (test sample 6 uptake group)

In the view of figure 13 of the drawings,

o: control sample intake group

■ : test sample 8 uptake group

In the view of figure 14 of the drawings,

o: control sample intake group

■ : test sample 8 uptake group

Claims

1. A crystalline lens hardness regulator comprising glycosyl hesperetin as an active ingredient.

2. The lens hardness adjuster according to claim 1, which adjusts the hardness of the lens by suppressing hardening.

3. The lens hardness adjuster according to claim 1, which adjusts the hardness of the lens by softening.

4. A lens hardness adjuster according to any one of claims 1 to 3, wherein the glycosyl hesperetin is 1 or 2 or more selected from hesperidin, α -glycosyl hesperidin and 7-O- β -glycosyl hesperetin.

5. The lens hardness modifier of claim 4, wherein said alpha-glycosyl hesperidin is alpha-glycosyl hesperidin.

6. The lens hardness modifier of any one of claims 1 to 5 for oral ingestion.

7. The lens hardness adjuster according to any one of claims 1 to 6, wherein the adjuster is used by continuously taking it for 4 days or more.

8. The lens hardness adjuster according to any one of claims 1 to 7, which is intended for an adult.

9. The lens hardness adjuster according to any one of claims 1 to 8, wherein lens hardening with age is prevented, alleviated and ameliorated.

10. Food, supplement, health food, health aid, health function food, nutritional aid, nutritional function food, functional representation food, specific health food, specific use food, quasi drug or pharmaceutical product comprising the lens hardness modifier according to any one of claims 1 to 9.

11. The composition of claim 10, wherein the reduction in focal length and/or near vision is prevented, alleviated, and ameliorated.

12. A method for adjusting the hardness of a lens, characterized by using glycosyl hesperetin as an active ingredient.