JP7608707B2 - Myopia progression inhibitor, functional food and ophthalmic composition - Google Patents

Description

The present invention relates to a myopia progression inhibitor, a functional food, and an ophthalmic composition that contain omega-3 fatty acids and inhibit the progression of axial myopia.

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

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 in front of the retina. It is a symptom (hereinafter also referred to as "accommodative dysfunction") caused by temporary paralysis of the ciliary body due to eye fatigue (eye strain), accommodative spasm, accommodative tension, etc., which deteriorates the movement of the crystalline lens. This accommodative dysfunction has traditionally been called pseudomyopia, refractive myopia, and accommodative tension myopia, which are functional disorders based on temporary accommodative spasm and accommodative 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 spasm of the ciliary body and relax the tension of 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 will not return to the original state. The majority of myopic patients have axial myopia.

When axial myopia becomes severe, that is, when it reaches a state known as severe myopia, the degree of elongation of the eye axis increases. As a result, the retina and choroid are stretched backwards, increasing the stress 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.

It has been reported in the past that the methods of slowing the progression of myopia are atropine eye drops, pirenzepine eye ointment, orthokeratology, peripheral defocusing soft contact lenses, and progressive multifocal spectacles, in that order, with a statistically significant effect on slowing the progression of myopia. However, atropine eye drops have the problem of side effects, orthokeratology and other methods have issues with the cost and complexity of the procedure, and wearing spectacles has the issue of limited effectiveness, and all of these remain issues that must be resolved.

Patent document 1 presents 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 involves 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 for hyperopia in human males only.

WO2010/010365A1

The object of the present invention is to provide a myopia progression inhibitor, functional food, and ophthalmic composition that can inhibit the elongation of the axial length of the eye and inhibit the progression of axial myopia.

The inventor is developing technology that can inhibit the elongation of the axial length and inhibit the progression of axial myopia, as well as technology that can shorten the axial length to treat axial myopia. In the process, the inventor conducted an experiment in which mice were fed food containing omega-3 fatty acids and discovered that the elongation of the axial length was inhibited. Previously, it had been reported that omega-3 fatty acids are effective against hyperopia, but myopia, particularly axial myopia caused by elongation of the axial length, had not been studied. This invention is the first technology to demonstrate that omega-3 fatty acids are effective in inhibiting the elongation of the axial length and treating axial myopia.

The myopia progression inhibitor of 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 acids.

In the myopia progression inhibitor 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.

In the myopia progression inhibitor according to the present invention, it is preferable that the omega-3 fatty acid is extracted from one or more oils selected from linseed oil, perilla oil, and perilla oil.

The myopia progression inhibitor of the present invention is in the form of an orally ingested drug.

The functional food according to the present invention contains the myopia progression inhibitor according to the present invention.

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 axial myopia.

The present invention provides a myopia progression inhibitor, functional food, and ophthalmic composition that can inhibit the elongation of the axial length of the eye and inhibit the progression of axial myopia.

1 is a graph showing the change in axial length caused by the myopia progression inhibitor according to the present invention. 1 is a graph showing changes in refraction due to the myopia progression inhibitor according to the present invention. FIG. 1 is a schematic diagram of Experiment 2. This is a Volcano Plot for omega-3 and omega-6 fatty acids.

The myopia progression inhibitor, functional food, and ophthalmic composition according to the present invention are described in detail below. The present invention, including its gist, is not limited to the following embodiments, and includes modified examples and application examples.

[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.

Below is a detailed explanation of myopia progression inhibitors.

(Omega-3 fatty acids)
Omega-3 fatty acids include 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 these, one or more unsaturated fatty acids selected from α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid are preferred.

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. In particular, it is preferable that they are extracted from linseed oil. However, the effects of the present invention are not achieved with compositions containing omega-6 fatty acids extracted from soybean oil, sesame oil, sunflower oil, salad oil, corn oil, etc.

(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.

(functional foods)
The myopia progression inhibitor of the present invention can be a functional food containing omega-3 fatty acid.Functional foods can include health foods, functional foods, dietary supplements, nutritional functional foods, special purpose foods, specific health foods, or normal foods.Since these foods contain omega-3 fatty acid, they are effective for children and young people who are in the growth stage and are prone to the onset and progression of axial myopia.In addition, even if they are not these, they are also preferable for symptoms and diseases caused by axial elongation.

Foods can come in a variety of forms (health foods, nutritional supplements, etc.), including 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.

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.

<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 (a drug for inhibiting the progression of axial myopia), for treating axial myopia by shortening the axial length (a drug for treating axial myopia), and for preventing eye diseases caused by axial myopia (a drug 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.

The ophthalmic composition can be made into a pharmaceutical preparation by adding pharma- ceutical acceptable excipients, 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, or 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 preparation.

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 formulated with excipients, lubricants, binders, disintegrants, and the like, and additives such as preservatives, antioxidants, colorants, and sweeteners can also be used as needed. Liquid preparations can be formulated with solvents, dissolution aids, suspending agents, isotonicity agents, buffers, soothing agents, and the like, and additives such as preservatives, antioxidants, colorants, and sweeteners can also be used as needed.

The ophthalmic composition may be in the form of an eye drop such as an aqueous eye drop or a suspension eye drop. The eye drop may contain pharmacologically active ingredients, physiologically active ingredients, and other ingredients. Examples of such ingredients include congestion relief ingredients, ocular muscle regulating ingredients, anti-inflammatory ingredients, astringent ingredients, antihistamine ingredients, antiallergic ingredients, vitamins, amino acids, antibacterial ingredients, sugars, polymeric compounds or derivatives thereof, cellulose or derivatives thereof, local anesthetic ingredients, glaucoma treatment ingredients, and cataract treatment ingredients. The eye drop may further contain various additives such as carriers, fragrances or refreshing agents, preservatives, bactericides or antibacterial agents, pH regulators, chelating agents, stabilizers, isotonicity agents, buffers, and thickeners that are commonly used in the preparation of liquids.

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 who are still growing. In particular, it can suppress the decline in vision (the onset and progression of axial myopia), and is expected to have the 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, who are still growing.

The present invention will be explained in more detail with reference to examples.

[Experiment 1]
A myopia suppression experiment with omega-3 fatty acids was carried out 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-mixture of Domitor (Nihon Zenyaku Kogyo Co., Ltd.), Betorfal (Meiji Seika Pharma Co., Ltd.) and Midazolam (Sando Corporation), 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 was provided with a screw thread so that an adjustment tool could be fixed with a nut.

A -30 diopter (D) minus lens (Rainbow Contact, Rainbow Optical Laboratory Co., Ltd.) was placed on the right eye, and a 0D lens was placed on the left eye as a control. Next, the mice were fed an omega-6 fatty acid diet (AIN-93, 4% soybean oil, Oriental Yeast Co., Ltd.) or an omega-3 fatty acid diet (AIN-93, 4% linseed oil, Oriental Yeast Co., Ltd.) 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 fed at 12 g/kg/day. Measurements were performed on the axial length and refraction at 3 and 8 weeks of age.

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 of all the ingredients of the feed, and the omega-3 fatty acid feed had 4% linseed oil instead of 4% 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.

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 mix, 1.0% AIN-93 vitamin mix, 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, 500 mL) is the same as the omega-3 fatty acid feed except that the 4% linseed oil in the feed is replaced with 4% soybean oil, and 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 linseed oil is usually about 14.3% linoleic acid, 18.3% oleic acid, and about 53.4% linolenic acid. AIN-93 is a standard purified feed for nutritional research using mice and rats published by the National Institute of Nutrition (AIN) in 1993 (AIN-93). This feed is based on the nutritional requirements of mice and rats published by the National Academy of Sciences National Research Council (NAS-NRC), and the composition of this feed was determined by AIN using smooth growth, pregnancy, lactation, etc. for the first year after birth as an indicator.

(Measuring device)
Axial length was measured using a spectral domain optical coherence tomography (Envisu R4310, manufactured by Leica Corp.) Refraction was measured using an infrared photorefractor for mice.

(Test Reagents)
Midorin P (registered trademark, Santen Pharmaceutical Co., Ltd.) was used to stabilize the pupil during measurement. 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. Atipamezole hydrochloride (Antisedan/registered trademark, Nippon Zenyaku Kogyo Co., Ltd.) was used at the time of awakening from anesthesia.

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

[Experiment 2]
As in experiment 1, myopia in the myopia-induced eyes (-30D) was suppressed in mice fed the omega-3 fatty acid-rich diet. Therefore, in experiment 2, to investigate the effect of the diet containing omega-3 fatty acids in the eyeball, the eyeball was removed and subjected to liquid chromatography tandem mass spectrometry (LC-MS/MS), which can comprehensively capture lipid molecular species.

Figure 3 is an outline of experiment 2. The samples used were the same omega-3 fatty acid diet and omega-6 fatty acid diet as in experiment 1, with omega-3 fatty acid diet: 0D x 3 eyes, omega-3 fatty acid diet: -30D x 3 eyes, omega-6 fatty acid diet: 0D x 3 eyes, and omega-6 fatty acid diet: -30D x 3 eyes. Mice were fed each diet and euthanized after 5 weeks (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.

Figure 4 is a Volcano Plot comparing 340 types of lipids obtained by LC-MS/MS in eyes in which myopia was induced with -30D from the omega-3 fatty acid diet group and myopia was induced in eyes in 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.

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.

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 according to 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 (7)

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. 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. The myopia progression inhibitor according to claim 1 or 2, which is in the form of an oral dosage form. The myopia progression inhibitor according to any one of claims 1 to 3, which is used in growing children under the age of 20. A functional food containing the myopia progression inhibitor according to any one of claims 1 to 4, for inhibiting a decrease in refractive index and inhibiting the elongation of axial length. 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 . The ophthalmic composition according to claim 6 for inhibiting the progression or treating axial myopia or for preventing eye diseases caused by said axial myopia.

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