JP6784407B2 - Myopia preventive agent and myopia progression inhibitor - Google Patents

Description

The present invention relates to a myopia preventive agent and a myopia progression inhibitor.

It is reported that the myopic population is still increasing globally. Myopia includes refractive myopia and axial myopia, most of which are axial myopia. In axial myopia, myopia progresses with the extension of the axial length, and the extension is irreversible (Morgan IG et al., Lancet, 2012). As myopia progresses, it becomes severe myopia, and severe myopia is known to be the leading cause of blindness (Iwase A. et al., Ophthalmology, 2006). Therefore, there has been a strong demand for means for preventing the occurrence of myopia and for delaying the progression of myopia.

The present invention has been made for the purpose of providing a myopia preventive agent and a myopia progression inhibitor.

Metformin is a biguanide oral hypoglycemic agent that improves glucose metabolism by stimulating the intracellular transduction system via AMP-activated protein kinase (AMPK). The present inventors investigated the action of metformin using a chick that has been established as an animal experimental model for myopia, and found that it has an effect of suppressing eyeball length elongation, and completed the present invention.

One embodiment of the present invention is an eyeball length elongation inhibitor containing a compound having the following structural formula or a pharmaceutically acceptable salt thereof as an active ingredient.

(In the formula, R ₁ and R ₂ are groups independently selected from hydrogen and C1-6 alkyl groups which may be substituted with phenyl.)
Another embodiment of the present invention is a myopia preventive agent or a myopia progression inhibitor containing the above compound.

In the case of any drug, the compound may be metformin, buformin, or phenformin.

A further embodiment of the present invention is a myopia preventive agent or a myopia progression inhibitor containing an anti-aging agent as an active ingredient. The anti-aging agents include metformin, rapamycin, resveratrol, quercetin, icosapentaenoic acid (EPA), docosahexaenohydrogen (DHA), statin, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), and astaxanthin. , Angiotensin, EGCG (epigallocatechin-3-gallate), coenzyme Q10, spermin, spermidin, nicotinamide riboside, nicotinamide mononucleotide, SS31, glucosamine, or isoflavone.

A further embodiment of the present invention is a method for evaluating a myopia preventive agent or a myopia progression inhibitor, wherein a compound having the following structural formula or a pharmaceutically acceptable salt thereof is administered to the chick, and the chick. It is an evaluation method including a step of measuring the total eyeball length, the vitreous cavity length, or the axial length.

(In the formula, R _{1 to} R ₇ are groups independently selected from hydrogen and C1-6 alkyl groups which may be substituted with phenyl, respectively.)
A further embodiment of the present invention is a method for screening a myopia preventive agent or a myopia progression inhibitor, wherein the chick is administered with a compound having the following structural formula or a pharmaceutically acceptable salt thereof, and the chick. The step of measuring the total eye length, the vitreous cavity length, or the axial length to obtain the first measurement result, and the first measurement result are the total eye length of the control chick to which the compound or a salt thereof is not administered. , A step of comparing with the second measurement result obtained by measuring the vitreous cavity length or the axial length, and a compound or a salt thereof whose first measurement result is significantly shorter than the second measurement result. A screening method including a step of identifying and a step of using the identified compound or a salt thereof as a myopia preventive agent or a myopia progression inhibitor.

(In the formula, R _{1 to} R ₇ are groups independently selected from hydrogen and C1-6 alkyl groups which may be substituted with phenyl, respectively.)
== Cross-reference with related literature ==
This application claims the benefit of priority on the basis of Japanese Application No. Japanese Application No. 2015-089570 filed on April 24, 2015, which is incorporated herein by reference.

It is a figure which shows that metformin has a significant vitreous cavity length elongation inhibitory effect in one Example of this invention. Control eye: Shielded eye; Cover eye: Unshielded eye; Control: No metformin administration group; Metformin: Metformin administration group It is a figure which shows that metformin has a significant effect of suppressing axial length elongation in one Example of this invention. Control eye: Shielded eye; Cover eye: Unshielded eye; Control: No metformin administration group; Metformin: Metformin administration group

Hereinafter, embodiments of the present invention completed based on the above findings will be described in detail with reference to examples. The object, feature, advantage, and idea thereof of the present invention will be apparent to those skilled in the art from the description of the present specification, and those skilled in the art can easily reproduce the present invention from the description of the present specification. it can. The embodiments and specific examples of the invention described below show preferred embodiments of the present invention and are shown for illustration or explanation purposes, and the present invention is described in them. It is not limited. It will be apparent to those skilled in the art that various modifications and modifications can be made based on the description of this specification within the intent and scope of the present invention disclosed herein.
== Eyeball length elongation inhibitor Active ingredient of vitreous cavity length elongation inhibitor and axial length elongation inhibitor ==
The eyeball length elongation inhibitor, the vitreous cavity length elongation inhibitor, and the axial length elongation inhibitor according to the present invention have an eyeball length elongation inhibitory effect, a vitreous cavity length elongation inhibitory effect, and an axial length elongation inhibitory effect, respectively. , A compound having the following structural formula or a pharmaceutically acceptable salt thereof is contained as an active ingredient.

(In the formula, R ₁ and R ₂ are groups independently selected from hydrogen and C1-6 alkyl groups which may be substituted with phenyl.)
The phenyl group for phenyl substitution may be substituted with any hydrogen of the alkyl group, and the number of phenyl groups substituted in the alkyl group is not limited, but is 1 to 2 in one alkyl group. Is preferable.

The compound is preferably metformin, buformin, phenformin, or a salt thereof, most preferably metformin hydrochloride.

All of these compounds can be easily chemically synthesized by known methods.

This compound can be used as a myopia preventive agent or a myopia progression inhibitor because of its effect of suppressing eyeball length elongation.
== Composition of the drug according to the present invention ==
The agent according to the present invention may further contain various commonly used ingredients in addition to the active ingredient, for example, one or more pharmaceutically acceptable excipients, disintegrants, and the like. Diluents, lubricants, flavoring agents, coloring agents, sweeteners, flavoring agents, suspending agents, wetting agents, emulsifiers, dispersants, auxiliary agents, preservatives, buffers, binders, stabilizers, coating agents And so on.

The dosage form is not particularly limited, and for various dosage forms, for example, tablets, capsules, powders, granules, pills, liquids, emulsions, suspensions, solutions, syrups, It can be a syrup, an extract, or an elixir. Parenteral preparations include, for example, injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections; transdermal or patches, ointments or lotions; sublingual preparations for oral administration. , Oral patches; and aerosols for nasal administration; suppositories, but not limited to. These formulations can be produced by known methods commonly used in the formulation process. Further, the agent according to the present invention may be in a long-acting or sustained-release dosage form.

The amount of the active ingredient contained in the drug according to the present invention can be appropriately determined depending on the dose range of the active ingredient, the number of doses, and the like.
== How to use the agent according to the present invention ==
Since the agent according to the present invention has an effect of suppressing eyeball length elongation, it can be used as a myopia preventive agent or a myopia progression inhibitor.

For example, the myopia preventive agent can be administered to a normal individual who does not have myopia to prevent the individual from becoming myopia. In addition, the myopia progression inhibitor can suppress the progression of myopia by administering it to an individual who has become myopia (called a patient in the case of humans).

Here, the animal species of the individual to which the agent according to the present invention is administered is not particularly limited and may be a vertebrate, but is preferably a mammal, and most preferably a human.

The administration route of the drug according to the present invention can be selected from either systemic administration or topical administration. In addition, it can be administered by either an oral route or a parenteral route. Examples of the parenteral route include ordinary intravenous administration, intraarterial administration, and subcutaneous, intradermal, and intramuscular administration, but oral administration is preferable because administration is easy.

The dose range of the drug according to the present invention is not particularly limited, and the efficacy of the contained ingredients, the form of administration, the route of administration, the type of disease, the nature of the subject (body weight, age, medical condition and use of other medicines) It is appropriately selected depending on the presence or absence) and the judgment of the doctor in charge, but it is preferable to administer 500 to 2250 mg, preferably 750 to 1500 mg daily for human adults. The above dose can be administered once to several times a day.
== Myopia preventive agent or myopia progression inhibitor containing anti-aging agent ==
Metformin is known to exert an anti-aging function by inhibiting mTOR. Therefore, the myopia preventive agent or myopia progression inhibitor of the present invention may contain an anti-aging agent. The anti-aging agent is not particularly limited, but is rapamycin, resveratrol, quercetin, icosapentaenoic acid (EPA), docosahexaenohydrogen (DHA), statin, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist (ARB), Examples thereof include astaxanthin, angiotensin, EGCG (epigallocatechin-3-gallate), coenzyme Q10, spermin, spermidin, nicotinamide riboside, nicotinamide mononucleotide, SS31, glucosamine, and isoflavone.
== Evaluation method of myopia preventive agent or myopia progression inhibitor ==
The evaluation method according to the present invention is a method for evaluating a myopia preventive agent or a myopia progression inhibitor, which comprises a step of administering to a chick a compound having the following structural formula or a pharmaceutically acceptable salt thereof, and the chick. The step of measuring the total eye length, the vitreous cavity length, or the axial length is included.

(In the formula, R _{1 to} R ₇ are groups independently selected from hydrogen and C1-6 alkyl groups which may be substituted with phenyl, respectively. R _{1 to} R ₄ are all hydrogen. The phenyl group for phenyl substitution may be substituted with any hydrogen of the alkyl group, and the number of substitutions in the alkyl group is not limited, but 1 to 2 in one alkyl group. It is preferably individual.

The chick may be a model of myopia progression. As a method for producing a model of the progression of myopia of a chick, a conventionally known method may be used, and when one or both eyes of a chick are occluded, the shielded eye becomes myopia. Therefore, total eye length, vitreous cavity length, or axial length is measured for the shielded eye.
== Screening method for myopia preventive agent or myopia progression inhibitor ==
The screening method according to the present invention is a method for screening a myopia preventive agent or a myopia progression inhibitor, which comprises a step of administering a compound having the following structural formula or a pharmaceutically acceptable salt thereof to a chick, and the chick. The step of measuring the total eyeball length, the vitreous cavity length, or the axial length to obtain the first measurement result, and the first measurement result are administered with a compound having the following structural formula or a pharmaceutically acceptable salt thereof. The step of measuring the total ocular length, the vitreous cavity length, or the axial length of the non-controlling chick and comparing it with the second measurement result, and the first measurement result is longer than the second measurement result. Includes a step of identifying a compound or a salt thereof that is significantly shorter, and a step of using the identified compound or a salt thereof as a myopia preventive agent or a myopia progression inhibitor.

(In the formula, R _{1 to} R ₇ are groups independently selected from hydrogen and C1-6 alkyl groups which may be substituted with phenyl, respectively. R _{1 to} R ₄ are all hydrogen. The phenyl group for phenyl substitution may be substituted with any hydrogen of the alkyl group, and the number of substitutions in the alkyl group is not limited, but 1 to 2 in one alkyl group. It is preferably individual.

The chick may be a model of myopia progression. As a method for producing a model of the progression of myopia of a chick, a conventionally known method may be used, and when one or both eyes of a chick are occluded, the shielded eye becomes myopia. Therefore, total eye length, vitreous cavity length, or axial length is measured for the shielded eye.

<Example 1>

It is known that when one eye of a chick is covered with a transparent hemisphere, the eye (shielded eye) becomes myopic in about one week, and it is used as a model of myopia progression (for example, Seko et al., Invest). . Ophthalmol. Vis. Sci. May 1995 vol. 36 no. 6 1183-1187).

A total of 23 chicks (White Leghorn species) on the second day after birth were shielded from one eye and divided into the following four groups. As metformin, 1,1-Dimethylbiguanide hydrochloride (Sigma-Aldrich), which is a metformin hydrochloride, was used. As for the dose, 300-600 mg / kg / day was administered in the previous report of oral administration of metformin in chickens (Ashwell CM, et al. Poult Sci, 2003), and the dose was used as a reference.
(A) No drug administration (5 birds, no administration group below)
(B) Metformin 250 mg / kg / day, 7 days continuous administration (6 birds, hereafter 250 mg / kg / day administration group)
(C) Metformin 500 mg / kg / day, 7 days continuous administration (6 birds, hereinafter 500 mg / kg / day administration group)
(D) Metformin 1000 mg / kg / day, 7 days continuous administration (6 birds, hereinafter 1000 mg / kg / day administration group)
After breeding under the above conditions for 1 week with one eye shielded, the eyeballs of the chicks were removed and the total eyeball length was measured with a caliper. The average value of the results is shown in Table 1. The vitreous cavity length and axial length were also measured, and the average values thereof are shown in Table 2. The Tukey HSD test was used for statistical processing.

As a result, the average total eye length was significantly (p <0.05) in the shielded eyes in all the other administration groups as compared with the non-administration group. In addition, even with unshielded eyes, the values were 9.68 mm, 9.17 mm, 9.17 mm, and 8.98 mm, respectively, and the 250 mg / kg / day administration group and the 500 mg / kg / day administration group tended to suppress eye length elongation compared to the non-administration group. In the 1000 mg / kg / day administration group, there was a significant (p <0.05) effect of suppressing eye length elongation. On the other hand, the vitreous cavity length and the axial length were not significantly different between the administration group and the non-administration group, but there is a possibility that the vitreous cavity length and the axial length elongation are suppressed.
<Example 2>

A total of 17 chicks (White Leghorn species) on the second day after birth were bred until the fifth day after birth with one eye shielded, and divided into the following two groups. The same metformin as in Example 1 was used.
(A) Saline administration, no drug administration (8 birds, no administration group below)
(B) Metformin (500 mg / kg / day) -containing physiological saline was continuously administered every morning from the 6th day (9 birds, hereinafter 500 mg / kg / day administration group).
After breeding under the above conditions for 7 days with one eye shielded, the eyeballs of the chicks were removed, the vitreous cavity length and the axial length were measured with calipers, and B-mode analysis was performed. The results are shown in FIGS. 1 and 2, respectively. The Mann-Whitney U test was used for statistical processing.

As a result, as shown in FIGS. 1 and 2, the vitreous cavity length was significantly (p <0.05) extended in the shielded eye as compared with the unshielded eye. Metformin had a significant effect of suppressing vitreous cavity length and axial length elongation in both shielded and unshielded eyes.
<Conclusion>
As described above, metformin has an eyeball length elongation inhibitory effect and is effective as a myopia preventive agent and a myopia progression inhibitor.

That is, a compound having the following structural formula or a pharmaceutically acceptable salt thereof, including metformin, buformin, and phenformin, is effective as a myopia preventive agent and a myopia progression inhibitor.

(In the formula, R ₁ and R ₂ are groups independently selected from hydrogen and C1-6 alkyl groups which may be substituted with phenyl.)
In addition, metformin also has a vitreous cavity length elongation inhibitory effect and an axial length elongation inhibitory effect.

The present invention has made it possible to provide a myopia preventive agent and a myopia progression inhibitor.

Claims (5)

An eye length elongation inhibitor containing metformin, buformin, or phenformin or a pharmaceutically acceptable salt thereof as an active ingredient. A myopia preventive agent containing metformin, buformin, or phenformin or a pharmaceutically acceptable salt thereof as an active ingredient. A myopia progression inhibitor containing metformin, buformin, or phenformin or a pharmaceutically acceptable salt thereof as an active ingredient. A method for evaluating a myopia preventive agent or a myopia progression inhibitor, which comprises a step of administering a compound having the following structural formula or a pharmaceutically acceptable salt thereof to a chick, and the total eyeball length and vitreous cavity length of the chick. Alternatively, an evaluation method including a step of measuring the axial length.
(In the formula, R _{1 to} R ₇ are groups independently selected from hydrogen and C1-6 alkyl groups which may be substituted with phenyl, respectively.) A method for screening a myopia preventive agent or a myopia progression inhibitor, wherein a compound having the following structural formula or a pharmaceutically acceptable salt thereof is administered to a chick, and the total eyeball length and the vitreous cavity length of the chick. Alternatively, the step of measuring the axial length and obtaining the first measurement result, and the first measurement result, the total eye length, the vitreous cavity length, or the axial axis of the control chick to which the compound or a salt thereof has not been administered. A step of measuring the length and comparing it with the second measurement result obtained, a step of identifying a compound whose first measurement result is significantly shorter than the second measurement result or a salt thereof, and a specified compound. A screening method comprising the step of using the salt as a myopia preventive agent or a myopia progression inhibitor.
(In the formula, R _{1 to} R ₇ are groups independently selected from hydrogen and C1-6 alkyl groups which may be substituted with phenyl, respectively.)