Myopia progression inhibitor, functional food and ophthalmic composition

Abstract

To provide myopia progression inhibitors, functional foods, and ophthalmic compositions which can inhibit the elongation of myopia axial length to inhibit the progression of axial myopia.SOLUTION: The elongation of an eye axial length is inhibited by a composition containing omega-3 fatty acid. The omega-3 fatty acid is preferably one or more unsaturated fatty acids selected from α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, and is preferably extracted from one or more oils selected from linseed oil, perilla oil, and perilla oil. Preferably the dosage form is an oral ingestion agent.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a myopia progression inhibitor, a functional food, and an ophthalmic composition which contain omega-3 fatty acids and inhibit the progression of axial myopia. [Background technology]

[0002] It is said that East Asians have a higher rate of myopia than Westerners, and at least one-third of the Japanese population, or about 40 million people, are myopic. Despite this, the molecular mechanisms behind the onset and progression of myopia have not been elucidated at all, and although correction is possible with glasses and contact lenses, there is no fundamental treatment.

[0003] Myopia is a condition in which the focus is not clear because the light is focused in front of the retina. There are two main types of myopia: refractive myopia, which occurs when the refractive index of the cornea or crystalline lens is too strong, and axial myopia, which occurs when the axial length of the eyeball, which is the length of the eyeball in the front-to-back direction, is too long. Refractive myopia is a condition in which the lens, which acts as a lens, is unable to adjust its thickness properly and focuses the light in front of the retina. This condition occurs when the ciliary body is temporarily paralyzed due to eye fatigue (eye strain), accommodation spasm, accommodation tension, etc., causing the movement of the crystalline lens to deteriorate (hereinafter also referred to as "accommodative dysfunction"). This accommodative dysfunction has traditionally been called pseudomyopia, refractive myopia, and accommodation tension myopia, which are functional disorders based on temporary accommodation spasm and accommodation tension. Ignoring the symptoms will not lead to myopia, and can be improved by resting the eyes, or by using eye drops to stop the ciliary body spasm and relax the crystalline lens. On the other hand, axial myopia is a condition in which the axial length of the eye is so long that even if the lens is adjusted to be sufficiently thin, the focus is in front of the retina, and is irreversible and cannot be restored to its original state. The majority of myopic patients have axial myopia.

[0004] When axial myopia becomes severe, that is, when it reaches a state known as high myopia, the degree of elongation of the eye axis increases. As a result, the retina and choroid are stretched backwards, increasing the load on them and causing various abnormalities in the fundus. A condition in which abnormalities occur in the fundus is called pathological myopia, and is one of the leading causes of blindness in developed countries. Although pathological myopia can lead to blindness, there is currently no effective treatment, and the establishment of a treatment is desired.

[0005] It has been reported in the past that the means of suppressing the progression of myopia are atropine eye drops, pirenzepine eye ointment, orthokeratology, peripheral defocusing soft contact lenses, and progressive multifocal glasses, in that order, with statistically significant effects on suppressing the progression of myopia. However, atropine eye drops have the problem of side effects, orthokeratology and other methods have the problem of cost burden and complicated procedures, and wearing glasses has the problem of limited effectiveness, and all of these remain issues that need to be resolved.

[0006] Patent Document 1 proposes a method for preventing or treating visual impairment in humans or non-human mammals, which can improve hyperopia by strengthening the intraocular or extraocular muscle tissue of the subject. This method is a method of administering polyunsaturated fatty acid (PUFA) derivatives, particularly omega-3 fatty acid derivatives such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and has been verified only for hyperopia in human males. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO2010 / 010365A1 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a myopia progression inhibitor, a functional food, and an ophthalmic composition that can inhibit the elongation of the axial length and thereby inhibit the progression of axial myopia. [Means for solving the problem]

[0009] The present inventor is developing a technology that can suppress the elongation of the axial length and suppress the progression of axial myopia, and a technology that shortens the axial length to treat axial myopia. In the process, the inventor conducted an experiment by feeding mice food containing omega-3 fatty acids, and discovered that the elongation of the axial length was suppressed. Conventionally, it has been reported that omega-3 fatty acids are effective for hyperopia, but myopia, especially axial myopia caused by the elongation of the axial length, has not been studied. The present invention is the first technology to demonstrate that omega-3 fatty acids are effective for suppressing the elongation of the axial length and treating axial myopia.

[0010] The myopia progression inhibitor according to the present invention is an inhibitor of axial myopia progression that inhibits the elongation of the axial length of the eye, and is characterized by containing omega-3 fatty acid.

[0011] In the agent for inhibiting the progression of myopia according to the present invention, the omega-3 fatty acid is preferably one or more unsaturated fatty acids selected from α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid.

[0012] In the myopia progression inhibitor according to the present invention, the omega-3 fatty acids are preferably extracted from one or more oils selected from linseed oil, perilla oil, and perilla oil.

[0013] The agent for inhibiting the progression of myopia according to the present invention is in the form of an orally ingested agent.

[0014] The functional food according to the present invention contains the above-mentioned myopia progression inhibitor according to the present invention.

[0015] The ophthalmic composition according to the present invention is characterized by containing omega-3 fatty acids. This ophthalmic composition inhibits the progression or treats axial myopia, or prevents eye diseases caused by said axial myopia. Effect of the Invention

[0016] According to the present invention, it is possible to provide a myopia progression inhibitor, a functional food, and an ophthalmic composition that can inhibit the elongation of the axial length and inhibit the progression of axial myopia. [Brief description of the drawings]

[0017] [Figure 1] 1 is a graph showing the change in axial length caused by the myopia progression inhibitor according to the present invention. [Diagram 2] 1 is a graph showing changes in refraction due to the myopia progression inhibitor according to the present invention. [Diagram 3] FIG. 1 is a schematic diagram of Experiment 2. [Figure 4] This is a Volcano Plot about omega-3 and omega-6 fatty acids. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The myopia progression inhibitor, functional food, and ophthalmic composition according to the present invention will be described in detail below. The present invention, including its gist, is not limited to the following embodiments, and includes modifications and application examples.

[0019] [Myopia progression inhibitor] The myopia progression inhibitor of the present invention is an axial myopia progression inhibitor that inhibits the elongation of the axial length of the eye, and contains omega-3 fatty acid. This myopia progression inhibitor is an invention based on the results of the first demonstration that omega-3 fatty acid is effective in inhibiting the elongation of the axial length of the eye. Conventionally, it has been reported that omega-3 fatty acid is effective for hyperopia, but the present inventor has discovered a new effect that omega-3 fatty acid can inhibit the elongation of the axial length of the eye and inhibit the progression of axial myopia.

[0020] Hereinafter, the myopia progression inhibitor will be described in detail.

[0021] (Omega-3 fatty acids) The omega-3 fatty acids are alpha-linolenic acid (ALA, all-cis-9,12,15-octadecatrienoic acid), stearidonic acid (STD, all-cis-6,9,12,15-octadecatrienoic acid), eicosatrienoic acid (ETE, all-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA, all-cis-8,11,14,17-eicosatetraenoic acid), and eicosapentaenoic acid (EPA, all-cis-5,8,11,14,17- eicosapentaenoic acid), docosapentaenoic acid (DPA, all-cis-7,10,13,16,19-docosapentaenoic acid), docosahexaenoic acid (DHA, all-cis-4,7,10,13,16,19-docosahexaenoic acid), tetracosapentaenoic acid (all-cis-9,12,15,18,21-tetracosapentaenoic acid), tetracosahexaenoic acid (herring acid, all-cis-6,9,12,15,18,21-tetracosahexaenoic acid). Among them, one or more unsaturated fatty acids selected from α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid are preferable.

[0022] These omega-3 fatty acids can be obtained from seafood, plants, and animal fats, and are preferably extracted from one or more oils selected from, for example, linseed oil, perilla oil, and perilla oil. Particularly, they are preferably extracted from linseed oil. However, the effect of the present invention is not achieved with a composition containing omega-6 fatty acids extracted from soybean oil, sesame oil, sunflower oil, salad oil, corn oil, etc.

[0023] (Dosage form, etc.) The dosage form of the myopia progression inhibitor is not particularly limited, but is preferably an oral intake agent. The dosage form is preferably an oral medication such as a tablet or capsule. On the other hand, it may be administered locally, but in that case, a drug delivery system (DDS) must be used.

[0024] (Functional food) The myopia progression inhibitor of the present invention can be a functional food containing omega-3 fatty acid. Examples of functional foods include health foods, functional foods, dietary supplements, nutritional functional foods, special purpose foods, specific health foods, and regular foods. These foods contain omega-3 fatty acid, so they are effective for children and young people who are growing and who are prone to the onset and progression of axial myopia. In addition, they are also preferable for symptoms and diseases caused by axial elongation.

[0025] Examples of the form of food include liquids such as juice, soft drinks, energy drinks, and tea; solids such as biscuits, tablets, granular powders, powders, and capsules; and semi-liquids such as pastes, jellies, soups, seasonings, and dressings (health foods, nutritional supplements, etc.).

[0026] Furthermore, foods that can be provided containing the myopia progression inhibitor of the present invention include supplements (powders, granules, soft capsules, hard capsules, tablets, chewable tablets, rapidly disintegrating tablets, syrups, liquids, etc.). The myopia progression inhibitor of the present invention can also be added to food for animals such as pets. Additives that are added to general foods, etc. can be added to the foods as necessary.

[0027] <Ophthalmic composition> The ophthalmic composition according to the present invention can be used as a medicine. The medicine containing the ophthalmic composition is used for inhibiting the elongation of the axial length (medicine for inhibiting the progression of axial myopia), for treating axial myopia by shortening the axial length (medicine for treating axial myopia), and for preventing eye diseases caused by axial myopia (medicine for preventing eye diseases caused by axial myopia). It is particularly preferable as a medicine for children and young people in the growth stage who are prone to the onset and progression of axial myopia.

[0028] The ophthalmic composition can be made into a pharmaceutical preparation by adding a pharma- ceutical acceptable excipient, etc. The pharmaceutical preparation is not particularly limited, and can be an oral preparation (solid preparations such as tablets, capsules, granules, fine granules, powders, chewable tablets, and lozenges, and liquid preparations such as liquids and syrups), eye drops, injections, etc. Among these, oral preparations and eye drops are preferred from the viewpoint of easily achieving the effects of the present invention. The ophthalmic composition according to the present invention can contain various additives according to the properties, applications, etc. of each.

[0029] Oral preparations include, for example, solid preparations such as tablets, capsules, granules, and powders, and liquid preparations such as syrups and drinks. Solid preparations can be blended with excipients, lubricants, binders, disintegrants, and the like, and additives such as preservatives, antioxidants, colorants, and sweeteners can be used as needed. Liquid preparations can be blended with solvents, dissolution aids, suspending agents, isotonicity agents, buffers, soothing agents, and the like, and additives such as preservatives, antioxidants, colorants, and sweeteners can be used as needed.

[0030] The ophthalmic composition may be an eye drop such as an aqueous eye drop or a suspension eye drop. The eye drop may contain a pharmacologically active ingredient, a physiologically active ingredient, or the like. Examples of such ingredients include a congestion relief ingredient, an ocular muscle regulating ingredient, an anti-inflammatory ingredient, an astringent ingredient, an antihistamine ingredient, an antiallergic ingredient, vitamins, amino acids, an antibacterial ingredient, sugars, a polymeric compound or a derivative thereof, cellulose or a derivative thereof, a local anesthetic ingredient, a glaucoma treatment ingredient, and a cataract treatment ingredient. The eye drop may further contain various additives such as a carrier, a flavoring or a refreshing agent, a preservative, a bactericide or an antibacterial agent, a pH regulator, a chelating agent, a stabilizer, an isotonicity agent, a buffer, and a thickening agent that are generally used in the preparation of liquids.

[0031] As described above, the myopia progression inhibitor or functional food (including foods for specified health uses, etc.) according to the present invention is effective for ages where axial myopia develops or progresses, particularly for children and young people in the growth stage. In particular, it can suppress the decline in vision (the onset and progression of axial myopia), and is expected to have an action effect of suppressing the elongation of the axial length that is likely to occur mainly in children under 20 years old and young people in their 20s to 30s, preferably 2 to 15 years old, and more preferably 6 to 12 years old, in the growth stage. EXAMPLES

[0032] The present invention will now be described in more detail with reference to examples.

[0033] [Experiment 1] A myopia suppression experiment with omega-3 fatty acids was conducted using a myopia model animal. Mice (C57BL / 6J mice, male, 3 weeks old) were used as myopia model animals. The mice were anesthetized with a triple-anesthesia mixture of Domitor (Nihon Zenyaku Kogyo Co., Ltd.), Betorfal (Meiji Seika Pharma Co., Ltd.), and Midazolam (Sandoz Co., Ltd.), and the skull was exposed with scissors. A post was erected on the skull and fixed with dental cement (Super-Bond, Sun Medical Co., Ltd.). The post had a screw thread so that an adjustment tool could be fixed with a nut.

[0034] A minus lens of -30 diopter (D) (Rainbow Contact, Rainbow Optical Laboratory Co., Ltd.) was attached to the right eye, and a lens of 0D was attached to the left eye as a control. Next, an omega-6 fatty acid diet (AIN-93, 4% soybean oil, manufactured by Oriental Yeast Co., Ltd.) or an omega-3 fatty acid diet (AIN-93, 4% linseed oil, manufactured by Oriental Yeast Co., Ltd.) was given to the mice from 3 to 8 weeks of age. The mice were kept in a light environment for 12 hours and a dark environment for 12 hours. The omega-6 fatty acid diet and the omega-3 fatty acid diet were given at a dose of 12 g / kg / day. Measurements were performed for axial length and refraction at 3 and 8 weeks of age, respectively.

[0035] In this experiment 1, both the omega-3 fatty acid feed and the omega-6 fatty acid feed were 4% oil, the omega-6 fatty acid feed was 4% soybean oil, and the omega-3 fatty acid feed was 4% linseed oil instead of soybean oil. The ratio of the omega-6 fatty acid feed to the omega-3 fatty acid feed for soybean oil and linseed oil was 5:1 for soybean oil and 1:3.7 for linseed oil. There are various methods for refining oil, and the composition ratio can be adjusted as desired depending on the method.

[0036] In detail, the omega-3 fatty acid feed (AIN-93, 4% linseed oil, manufactured by Oriental Yeast Co., Ltd.) is composed of 14.0% casein, 0.18% L-cystine, 46.5692% corn starch, 15.5% α-corn starch, 10.0% sucrose, 4.0% linseed oil, 5.0% cellulose powder, 3.5% AIN-93M mineral mixture, 1.0% AIN-93 vitamin mixture, 0.25% choline bitartrate, and 0.0008% tert-butylhydroquinone. On the other hand, the omega-6 fatty acid feed (AIN-93, 4% soybean oil, manufactured by Oriental Yeast Co., Ltd., linseed oil: Wako Pure Chemical Industries, Ltd. Grade 1, 500mL) is the same as the omega-3 fatty acid feed except that the 4% linseed oil is replaced with 4% soybean oil. It is composed of 14.0% casein, 0.18% L-cystine, 46.5692% corn starch, 15.5% α-corn starch, 10.0% sucrose, 4.0% linseed oil, 5.0% cellulose powder, 3.5% AIN-93M mineral mixture, 1.0% AIN-93 vitamin mixture, 0.25% choline bitartrate, and 0.0008% tert-butylhydroquinone. The fatty acid composition of soybean oil is usually about 50% linoleic acid, a little over 20% oleic acid, and about 10% linolenic acid, while the fatty acid composition of flaxseed oil is usually about 14.3% linoleic acid, 18.3% oleic acid, and about 53.4% ​​linolenic acid. AIN-93 is a standard purified diet for nutritional research using mice and rats published by the National Institute of Nutrition (AIN) in 1993 (AIN-93). This diet was determined by AIN based on the nutritional requirements of mice and rats published by the National Academy of Sciences National Research Council (NAS-NRC) and with the aim of ensuring smooth growth, pregnancy, lactation, etc. for the first year after birth.

[0037] (Measuring Equipment) Axial length was measured using a spectral domain optical coherence tomography (Envisu R4310, Leica), and refractive index was measured using an infrared photorefractor for mice.

[0038] (Test Reagents) Midorin P (registered trademark, Santen Pharmaceutical Co., Ltd.) was used to stabilize the pupil during measurement. In addition, a triple-mix anesthesia (medetomidine hydrochloride (Domitor / registered trademark, Nippon Zenyaku Kogyo Co., Ltd.), midazolam (Dormicum / registered trademark, Astellas Pharma Inc.), and butorphanol tartrate (Betorfal / registered trademark, Meiji Seika Co., Ltd.) was used for anesthesia recovery. Atipamezole hydrochloride (Antisedan / registered trademark, Nippon Zenyaku Kogyo Co., Ltd.) was used for anesthesia recovery.

[0039] (result) From the results of Figures 1 and 2, the refraction of the omega-6 fatty acid diet group was significantly myopic when wearing -30D, whereas myopia was significantly suppressed even when wearing -30D in the omega-3 fatty acid diet group. In addition, the axial length of the eye was significantly longer at -30D in the omega-6 fatty acid diet group, whereas it was significantly suppressed even when wearing -30D in the omega-3 fatty acid diet group. From these results, it was confirmed that omega-3 fatty acids are effective in suppressing myopia. Regarding the significance, a Welch-t test was performed, and * indicates p<0.05 (significant difference), ** indicates p<0.01 (highly significant difference).

[0040] [Experiment 2] As in experiment 1, mice that consumed a diet rich in omega-3 fatty acids had suppressed myopia in myopia-induced eyes (-30D). Therefore, in experiment 2, to investigate the effect of the diet containing omega-3 fatty acids in the eyeball, the eyeballs were enucleated and liquid chromatography tandem mass spectrometry (LC-MS / MS), which can comprehensively capture lipid molecular species, was performed.

[0041] Figure 3 is an outline of experiment 2. The samples were fed the same omega-3 and omega-6 fatty acid diets as in experiment 1, with omega-3 fatty acid diet: 0D·3 eyes, omega-3 fatty acid diet: -30D·3 eyes, omega-6 fatty acid diet: 0D·3 eyes, and omega-6 fatty acid diet: -30D·3 eyes. Mice were fed each diet, and euthanized 5 weeks later (at age 8 weeks). The eyeballs were frozen in liquid nitrogen and stored at -80°C. Lipids were extracted from the stored eyeballs, and the supernatant of the extract was transferred to a glass vial and analyzed by LC-MS / MS.

[0042] Figure 4 is a Volcano Plot comparing 340 types of lipids obtained by LC-MS / MS in eyeballs in which myopia was induced with -30D from the omega-3 fatty acid diet group and myopia was induced in eyes from the omega-6 fatty acid diet group. In this graph, 10 types of lipids (EPA, DPA-containing fatty acids) are shown in the upper right, and 3 types of lipids (AA, DTA-containing fatty acids) are shown in the upper left. The 10 types of lipids in the upper right show an increase in association with the myopia progression inhibition effect, and the 3 types of lipids in the upper left show a decrease in association with the myopia progression inhibition effect.

[0043] In this experiment 2, the omega-3 fatty acid diet group, in which myopia induction suppressed axial elongation and refractive decline, had an increase in EPA- and DPA-containing phospholipids and a decrease in AA- and DTA-containing phospholipids compared to the omega-6 fatty acid diet group, in which myopia induction was not suppressed. These findings suggest that, among omega-3 fatty acids, EPA has a myopia-suppressing effect. [Industrial Applicability]

[0044] It has been revealed that omega-3 fatty acids suppress the progression of axial myopia, for which there has been no effective treatment until now. The myopia progression inhibitor of the present invention is expected to be a treatment for axial myopia that not only suppresses the progression of axial myopia, but also shortens the axial length.

Claims

1. An agent for inhibiting the progression of axial myopia, which inhibits a decrease in refractive index and inhibits an elongation of axial length, comprising α-linolenic acid.

2. 2. The myopia progression inhibitor according to claim 1, wherein the α-linolenic acid is extracted from one or more oils selected from linseed oil, perilla oil, and perilla oil.

3. 3. The agent for inhibiting the progression of myopia according to claim 1 or 2, which is in the form of an oral dosage form.

4. The agent for inhibiting the progression of myopia according to any one of claims 1 to 3, which is used for growing children under 20 years of age.

5. A functional food for inhibiting a decrease in refractive index and inhibiting an elongation of the axial length, comprising the agent for inhibiting the progression of myopia according to any one of claims 1 to 4.

6. An ophthalmic composition for suppressing a decrease in refractive index and suppressing an elongation of the axial length, the ophthalmic composition comprising α-linolenic acid.

7. The ophthalmic composition according to claim 6, for inhibiting the progression or treating axial myopia, or for preventing an eye disease caused by said axial myopia.

Images