JPWO2016171282A1 - Myopia prevention agent and myopia progression inhibitor - Google Patents
Myopia prevention agent and myopia progression inhibitor Download PDFInfo
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- JPWO2016171282A1 JPWO2016171282A1 JP2017514230A JP2017514230A JPWO2016171282A1 JP WO2016171282 A1 JPWO2016171282 A1 JP WO2016171282A1 JP 2017514230 A JP2017514230 A JP 2017514230A JP 2017514230 A JP2017514230 A JP 2017514230A JP WO2016171282 A1 JPWO2016171282 A1 JP WO2016171282A1
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Abstract
本発明は、近視予防剤及び近視進行抑制剤を提供することを目的とする。すなわち、下記構造式を有する化合物またはその薬学的に受容できる塩を有効成分として含有する近視予防剤または近視進行抑制剤とする。
【化１】
（式中、Ｒ１及びＲ２は、水素、及びフェニル置換してもよいＣ１−６アルキル基から独立して選択される基である。）An object of the present invention is to provide a myopia preventive agent and a myopia progression inhibitor. That is, a myopia preventive agent or a myopia progression inhibitor containing a compound having the following structural formula or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical 1]
(In the formula, R 1 and R 2 are groups independently selected from hydrogen and a C 1-6 alkyl group which may be phenyl-substituted.)
Description
本発明は、近視予防剤及び近視進行抑制剤に関する。 The present invention relates to a myopia preventive agent and a myopia progression inhibitor.
近視の人口は依然として世界的に増えていることが報告されている。近視には屈折近視と軸性近視があり、多くは軸性近視である。軸性近視においては、眼軸長の伸長に伴って近視が進行し、伸長は不可逆的である（Morgan IG et al., Lancet， 2012）。近視が進むと強度近視となり、強度近視は第一位の失明原因として知られている（Iwase A. et al., Ophthalmology, 2006）。そのため、近視発生を予防する手段や近視の進行を遅らせる手段が強く求められていた。 It is reported that the myopic population is still growing worldwide. Myopia includes refractive myopia and axial myopia, and many are axial myopia. In axial myopia, myopia progresses with increasing axial length and is irreversible (Morgan IG et al., Lancet, 2012). As myopia progresses, it becomes intense myopia, which is known as the leading cause of blindness (Iwase A. et al., Ophthalmology, 2006). Therefore, a means for preventing the occurrence of myopia and a means for delaying the progress of myopia have been strongly demanded.
本発明は、近視予防剤及び近視進行抑制剤を提供することを目的としてなされた。 The present invention was made for the purpose of providing a myopia preventive agent and a myopia progression inhibitor.
メトホルミンは、AMP-activated protein kinase (AMPK)を介した細胞内伝達系を刺激することにより糖代謝を改善するビグアナイド系経口血糖降下剤である。本発明者らは、近視の動物実験モデルとして確立されているヒヨコを用いてメトホルミンの作用を調べたところ、眼球長伸長抑制効果があることを見いだし、本発明を完成した。 Metformin is a biguanide oral hypoglycemic agent that improves glucose metabolism by stimulating the intracellular transmission system via AMP-activated protein kinase (AMPK). The present inventors examined the action of metformin using a chick established as an animal experimental model for myopia, and found that it had an effect of suppressing eye length elongation, and completed the present invention.
本発明の一実施態様は、下記構造式を有する化合物またはその薬学的に受容できる塩を有効成分として含有する眼球長伸長抑制剤である。 One embodiment of the present invention is an eyeball elongation inhibitor containing a compound having the following structural formula or a pharmaceutically acceptable salt thereof as an active ingredient.
（式中、Ｒ１及びＲ２は、水素、及びフェニル置換してもよいＣ１−６アルキル基から独立して選択される基である。）
本発明の他の実施形態は、上記化合物を含有する、近視予防剤または近視進行抑制剤である。(In the formula, R 1 and R 2 are groups independently selected from hydrogen and a C 1-6 alkyl group which may be phenyl-substituted.)
Another embodiment of the present invention is a myopia preventive or myopia progression inhibitor containing the above compound.
いずれの薬剤の場合も、上記化合物が、メトホルミン、ブホルミン、またはフェンホルミンであってもよい。 In any case, the compound may be metformin, buformin, or phenformin.
本発明のさらなる実施形態は、アンチ・エイジング剤を有効成分として含有する近視予防剤または近視進行抑制剤である。前記アンチ・エイジング剤が、メトホルミン、ラパマイシン、レスベラトロール、ケルセチン、イコサペンタエン酸（EPA）、ドコサヘキサ塩酸（DHA）、スタチン、アンギオテンシン変換酵素（ACE）阻害薬、アンギオテンシン受容体拮抗薬（ARB）、アスタキサンチン、アントシアニン、EGCG (epigallocatechin−3−gallate)、コエンザイムQ10、スペルミン、スペルミジン、ニコチンアミドリボシド、ニコチンアミドモノヌクレオチド、SS31、グルコサミン、またはイソフラボンであってもよい。 A further embodiment of the present invention is a myopia prevention agent or myopia progression inhibitor containing an anti-aging agent as an active ingredient. The anti-aging agent is metformin, rapamycin, resveratrol, quercetin, icosapentaenoic acid (EPA), docosahexahydrochloride (DHA), statin, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor antagonist (ARB), astaxanthin , Anthocyanins, EGCG (epigallocatechin-3-gallate), coenzyme Q10, spermine, spermidine, nicotinamide riboside, nicotinamide mononucleotide, SS31, glucosamine, or isoflavone.
本発明のさらなる実施形態は、近視予防剤または近視進行抑制剤の評価方法であって、ヒヨコに対し、下記構造式を有する化合物またはその薬学的に受容できる塩を投与する工程と、前記ヒヨコの全眼球長、硝子体腔長、または眼軸長を測定する工程と、を含む評価方法である。 A further embodiment of the present invention is a method for evaluating a myopia preventive or a myopia progression inhibitor, comprising administering to a chick a compound having the following structural formula or a pharmaceutically acceptable salt thereof, Measuring the total eyeball length, vitreous cavity length, or axial length.
（式中、Ｒ１〜Ｒ７は、それぞれ、水素、及びフェニル置換してもよいＣ１−６アルキル基から独立して選択される基である。）
本発明のさらなる実施形態は、近視予防剤または近視進行抑制剤のスクリーニング方法であって、ヒヨコに対し、下記構造式を有する化合物またはその薬学的に受容できる塩を投与する工程と、前記ヒヨコの全眼球長、硝子体腔長、または眼軸長を測定し、第１の測定結果を得る工程と、第１の測定結果を、前記化合物またはその塩を投与していない対照のヒヨコの全眼球長、硝子体腔長、または眼軸長を測定して得られた第２の測定結果と比較する工程と、第１の測定結果が第２の測定結果より長さが有意に短い化合物またはその塩を特定する工程と、特定した化合物またはその塩を近視予防剤または近視進行抑制剤とする工程と、を含むスクリーニング方法である。(In the formula, R 1 to R 7 are groups independently selected from hydrogen and a C 1-6 alkyl group which may be phenyl-substituted.)
A further embodiment of the present invention is a screening method for a myopia preventive agent or a myopia progression inhibitor, comprising administering to a chick a compound having the following structural formula or a pharmaceutically acceptable salt thereof, Measuring the total eyeball length, vitreous cavity length, or axial length and obtaining a first measurement result; and the first measurement result is the total eyeball length of a control chick not administered with the compound or a salt thereof. Comparing the second measurement result obtained by measuring the vitreous cavity length or the axial length, and a compound or salt thereof in which the first measurement result is significantly shorter than the second measurement result. A screening method comprising a step of specifying, and a step of using the specified compound or a salt thereof as a myopia preventive agent or a myopia progression inhibitor.
（式中、Ｒ１〜Ｒ７は、それぞれ、水素、及びフェニル置換してもよいＣ１−６アルキル基から独立して選択される基である。）
＝＝関連文献とのクロスリファレンス＝＝
本出願は、平成２７年４月２４日出願の日本国出願番号特願２０１５-０８９５７０を基礎とする優先権の利益を主張し、これを引用することにより本明細書に含める。(In the formula, R 1 to R 7 are groups independently selected from hydrogen and a C 1-6 alkyl group which may be phenyl-substituted.)
== Cross reference with related literature ==
This application claims the benefit of priority based on Japanese Patent Application No. 2015-089570 filed on Apr. 24, 2015, and is incorporated herein by reference.
以下、上記知見に基づき完成した本発明の実施の形態を、実施例を挙げながら詳細に説明する。なお、本発明の目的、特徴、利点、及びそのアイデアは、本明細書の記載により、当業者には明らかであり、本明細書の記載から、当業者であれば、容易に本発明を再現できる。以下に記載された発明の実施の形態及び具体的に実施例などは、本発明の好ましい実施態様を示すものであり、例示又は説明のために示されているのであって、本発明をそれらに限定するものではない。本明細書で開示されている本発明の意図並びに範囲内で、本明細書の記載に基づき、様々な改変並びに修飾ができることは、当業者にとって明らかである。
＝＝眼球長伸長抑制剤硝子体腔長伸長抑制剤、及び眼軸長伸長抑制剤の有効成分＝＝
本発明にかかる眼球長伸長抑制剤、硝子体腔長伸長抑制剤、及び眼軸長伸長抑制剤は、それぞれ眼球長伸長抑制効果、硝子体腔長伸長抑制効果、及び眼軸長伸長抑制効果を有し、下記構造式を有する化合物またはその薬学的に受容できる塩を有効成分として含有する。Hereinafter, embodiments of the present invention completed based on the above knowledge will be described in detail with reference to examples. The objects, features, advantages, and ideas 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. It is not limited. It will be apparent to those skilled in the art that various modifications and variations can be made based on the description of the present specification within the spirit and scope of the present invention disclosed herein.
== Elongation inhibitor of eyeball length, inhibitor of vitreous cavity length elongation, and active ingredient of inhibitor of elongation of eye axis length ==
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 inhibiting effect, a vitreous cavity length elongation inhibiting effect, and an axial length elongation inhibiting effect, respectively. And a compound having the following structural formula or a pharmaceutically acceptable salt thereof as an active ingredient.
（式中、Ｒ１及びＲ２は、水素、及びフェニル置換してもよいＣ１−６アルキル基から独立して選択される基である。）
なお、フェニル置換するためのフェニル基は、アルキル基のいずれの水素と置換されてもよく、アルキル基中で置換される個数は限定されないが、１つのアルキル基中で１〜２個であることが好ましい。(In the formula, R 1 and R 2 are groups independently selected from hydrogen and a C 1-6 alkyl group which may be phenyl-substituted.)
The phenyl group for phenyl substitution may be substituted with any hydrogen of the alkyl group, and the number of substitution in the alkyl group is not limited, but is 1 to 2 in one alkyl group. Is preferred.
本化合物は、メトホルミン、ブホルミン、フェンホルミン、またはそれらの塩であることが好ましく、メトホルミン塩酸塩であることが最も好ましい。 The compound is preferably metformin, buformin, phenformin, or a salt thereof, most preferably metformin hydrochloride.
これらの化合物は、全て公知の方法で容易に化学合成可能である。 All of these compounds can be easily chemically synthesized by known methods.
この化合物は、その眼球長伸長抑制効果から、近視予防剤または近視進行抑制剤として使用することができる。
＝＝本発明に係る薬剤の構成＝＝
本発明に係る薬剤はまた、有効成分の他、必要に応じて、一般に用いられる各種成分をさらに含み得るものであり、例えば、１種以上の医薬的に許容され得る賦形剤、崩壊剤、希釈剤、滑沢剤、着香剤、着色剤、甘味剤、矯味剤、懸濁化剤、湿潤剤、乳化剤、分散剤、補助剤、防腐剤、緩衝剤、結合剤、安定剤、コーティング剤などを含み得る。This compound can be used as a myopia preventive agent or a myopia progression inhibitor because of its effect of suppressing eye length elongation.
== Composition of the drug according to the present invention ==
The drug according to the present invention can further contain various components that are generally used in addition to the active ingredient, if necessary. For example, one or more pharmaceutically acceptable excipients, disintegrants, Diluent, Lubricant, Flavor, Colorant, Sweetener, Flavoring Agent, Suspending Agent, Wetting Agent, Emulsifier, Dispersant, Auxiliary Agent, Preservative, Buffering Agent, Binder, Stabilizer, Coating Agent And so on.
剤形は、特に限定されず、種々の剤形、例えば、経口投与のためには、錠剤、カプセル剤、散剤、顆粒剤、丸剤、液剤、乳剤、懸濁液、溶液剤、酒精剤、シロップ剤、エキス剤、エリキシル剤とすることができる。非経口剤としては、例えば、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤などの注射剤；経皮投与または貼付剤、軟膏またはローション；口腔内投与のための舌下剤、口腔貼付剤；ならびに経鼻投与のためのエアゾール剤；坐剤とすることができるが、これらには限定されない。これらの製剤は、製剤工程において通常用いられる公知の方法により製造することができる。また本発明に係る薬剤は、持続性または徐放性剤形であってもよい。 The dosage form is not particularly limited, and various dosage forms such as tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, spirits, for oral administration, Syrups, extracts, and elixirs can be used. Examples of parenteral agents include injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections; transdermal administration or patches, ointments or lotions; sublingual agents for buccal administration Oral aerosol; as well as aerosols for nasal administration; suppositories, but not limited to. These preparations can be produced by known methods usually used in the preparation process. The drug according to the present invention may be a sustained or sustained release dosage form.
本発明に係る薬剤に含有される有効成分の量は、該有効成分の用量範囲や投薬の回数などにより適宜決定できる。
＝＝本発明に係る薬剤の使用方法＝＝
本発明に係る薬剤は、眼球長伸長抑制効果を有するので、近視予防剤または近視進行抑制剤として用いることができる。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 dosing, and the like.
== Method of using the drug according to the present invention ==
Since the agent according to the present invention has an effect of suppressing eye length elongation, it can be used as a myopia preventive agent or a myopia progression inhibitor.
例えば、近視予防剤は、近視を有しない正常個体に投与することにより、その個体が近視になることを予防できる。また、近視進行抑制剤は、いったん近視になった個体（ヒトの場合は患者と呼ばれる）に投与することにより、その近視の進行を抑制できる。 For example, an agent for preventing myopia can prevent the individual from becoming myopic when administered to a normal individual who does not have myopia. Moreover, the myopia progression inhibitor can suppress the progression of myopia by administering it to an individual who has once become myopic (referred to as a patient in the case of humans).
ここで、本発明に係る薬剤を投与する個体の動物種は特に限定されず、脊椎動物でもよいが、ほ乳類であることが好ましく、ヒトであることが最も好ましい。 Here, the animal species of the individual to which the drug 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.
本発明に係る薬剤の投与経路は、全身投与または局所投与のいずれも選択することができる。また、経口経路、非経口経路のいずれによっても投与できる。非経口経路としては、通常の静脈内投与、動脈内投与の他、皮下、皮内、筋肉内などへの投与を挙げることができるが、投与が容易なことから、経口投与が好ましい。 As the administration route of the drug according to the present invention, either systemic administration or local administration can be selected. Moreover, it can administer by any oral route or parenteral route. Examples of the parenteral route include normal intravenous administration, intraarterial administration, subcutaneous, intradermal, intramuscular administration and the like, but oral administration is preferable because administration is easy.
なお、本発明に係る薬剤の用量範囲は特に限定されず、含有される成分の有効性、投与形態、投与経路、疾患の種類、対象の性質（体重、年齢、病状および他の医薬の使用の有無など）、および担当医師の判断など応じて適宜選択されるが、ヒト成人には１日５００〜２２５０ｍｇ、好ましくは７５０〜１５００ｍｇを投与するのが好ましい。上記投与量は１日１回〜数回に分けて投与することができる。
＝＝アンチ・エイジング剤を含む近視予防剤または近視進行抑制剤＝＝
メトホルミンはｍＴＯＲを阻害することによって、アンチ・エイジング機能を発揮することが知られている。従って、本発明の近視予防剤または近視進行抑制剤は、アンチ・エイジング剤を含んでもよい。アンチ・エイジング剤は特に限定されないが、ラパマイシン、レスベラトロール、ケルセチン、イコサペンタエン酸（EPA）、ドコサヘキサ塩酸（DHA）、スタチン、アンギオテンシン変換酵素（ACE）阻害薬、アンギオテンシン受容体拮抗薬（ARB）、アスタキサンチン、アントシアニン、EGCG (epigallocatechin−3−gallate)、コエンザイムQ10、スペルミン、スペルミジン、ニコチンアミドリボシド、ニコチンアミドモノヌクレオチド、SS31、グルコサミン、イソフラボンなどが例示できる。
＝＝近視予防剤または近視進行抑制剤の評価方法＝＝
本発明にかかる評価方法は、近視予防剤または近視進行抑制剤の評価方法であって、ヒヨコに対し、下記構造式を有する化合物またはその薬学的に受容できる塩を投与する工程と、そのヒヨコの全眼球長、硝子体腔長、または眼軸長を測定する工程と、を含む。The dose range of the drug according to the present invention is not particularly limited, and the effectiveness of the contained components, administration form, administration route, type of disease, nature of the subject (weight, age, medical condition and use of other medicines) Or the like) and the judgment of the doctor in charge, etc., but it is preferable to administer 500-2250 mg, preferably 750-1500 mg per day for human adults. The above dose can be administered once to several times a day.
== An agent for preventing myopia or an agent for suppressing myopia progression including an anti-aging agent ==
Metformin is known to exhibit 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. Anti-aging agents are not particularly limited, but include rapamycin, resveratrol, quercetin, icosapentaenoic acid (EPA), docosahexahydrochloride (DHA), statins, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor antagonists (ARB), Examples include astaxanthin, anthocyanin, EGCG (epigallocatechin-3-gallate), coenzyme Q10, spermine, spermidine, nicotinamide riboside, nicotinamide mononucleotide, SS31, glucosamine, and isoflavone.
== Method for evaluating myopia preventive or myopia progression inhibitor ==
An evaluation method according to the present invention is a method for evaluating a myopia preventive or a myopia progression inhibitor, comprising administering a compound having the following structural formula or a pharmaceutically acceptable salt thereof to a chick, Measuring the total eyeball length, vitreous cavity length, or axial length.
（式中、Ｒ１〜Ｒ７は、それぞれ、水素、及びフェニル置換してもよいＣ１−６アルキル基から独立して選択される基である。Ｒ１〜Ｒ４は、全て水素であってもよい。）なお、フェニル置換するためのフェニル基は、アルキル基のいずれの水素と置換されてもよく、アルキル基中で置換される個数は限定されないが、１つのアルキル基中で１〜２個であることが好ましい。(In the formula, R 1 to R 7 are groups independently selected from hydrogen and a C 1-6 alkyl group which may be phenyl-substituted. R 1 to R 4 are all hydrogen. In addition, the phenyl group for phenyl substitution may be substituted with any hydrogen of the alkyl group, and the number of substitution in the alkyl group is not limited, but 1 to 2 in one alkyl group It is preferable that it is a piece.
ヒヨコは、近視進行のモデルであってもよい。ヒヨコの近視進行のモデルの作製方法は、従来知られた方法を用いればよく、ヒヨコの片目または両目を遮蔽すると、その遮蔽した眼が近視になる。従って、全眼球長、硝子体腔長、または眼軸長は、その遮蔽した眼について測定される。
＝＝近視予防剤または近視進行抑制剤のスクリーニング方法＝＝
本発明にかかるスクリーニング方法は、近視予防剤または近視進行抑制剤のスクリーニング方法であって、ヒヨコに対し、下記構造式を有する化合物またはその薬学的に受容できる塩を投与する工程と、そのヒヨコの全眼球長、硝子体腔長、または眼軸長を測定し、第１の測定結果を得る工程と、第１の測定結果を、下記構造式を有する化合物またはその薬学的に受容できる塩を投与していない対照のヒヨコの全眼球長、硝子体腔長、または眼軸長を測定して得られた第２の測定結果と比較する工程と、第１の測定結果が第２の測定結果より長さが有意に短い化合物またはその塩を特定する工程と、特定した化合物またはその塩を近視予防剤または近視進行抑制剤とする工程と、を含む。The chick may be a model of myopia progression. As a method for creating a model of chick myopia progression, a conventionally known method may be used. When one or both eyes of a chick are shielded, the shielded eyes become myopic. Thus, total eye length, vitreous cavity length, or axial length is measured for the occluded eye.
== Screening method for myopia prevention agent or myopia progression inhibitor ==
A screening method according to the present invention is a screening method for a myopia preventive agent or a myopia progression inhibitor, comprising administering to a chick a compound having the following structural formula or a pharmaceutically acceptable salt thereof, Measuring the total eyeball length, vitreous cavity length, or axial length, and obtaining a first measurement result, and administering the first measurement result to a compound having the following structural formula or a pharmaceutically acceptable salt thereof: Comparing the second measurement result obtained by measuring the total eyeball length, vitreous cavity length, or axial length of a control chick, and the first measurement result is longer than the second measurement result. Includes a step of identifying a compound or a salt thereof significantly shorter, and a step of using the identified compound or a salt thereof as a myopia prevention agent or a myopia progression inhibitor.
（式中、Ｒ１〜Ｒ７は、それぞれ、水素、及びフェニル置換してもよいＣ１−６アルキル基から独立して選択される基である。Ｒ１〜Ｒ４は、全て水素であってもよい。）なお、フェニル置換するためのフェニル基は、アルキル基のいずれの水素と置換されてもよく、アルキル基中で置換される個数は限定されないが、１つのアルキル基中で１〜２個であることが好ましい。(In the formula, R 1 to R 7 are groups independently selected from hydrogen and a C 1-6 alkyl group which may be phenyl-substituted. R 1 to R 4 are all hydrogen. In addition, the phenyl group for phenyl substitution may be substituted with any hydrogen of the alkyl group, and the number of substitution in the alkyl group is not limited, but 1 to 2 in one alkyl group It is preferable that it is a piece.
ヒヨコは、近視進行のモデルであってもよい。ヒヨコの近視進行のモデルの作製方法は、従来知られた方法を用いればよく、ヒヨコの片目または両目を遮蔽すると、その遮蔽した眼が近視になる。従って、全眼球長、硝子体腔長、または眼軸長は、その遮蔽した眼について測定される。 The chick may be a model of myopia progression. As a method for creating a model of chick myopia progression, a conventionally known method may be used. When one or both eyes of a chick are shielded, the shielded eyes become myopic. Thus, total eye length, vitreous cavity length, or axial length is measured for the occluded eye.
＜実施例１＞ <Example 1>
ヒヨコは、片目を透明半球で覆うと、約１週間でその眼（遮蔽眼）が近視化することが知られており、近視進行のモデルとして用いられている（たとえば、Seko et al., Invest. Ophthalmol. Vis. Sci. May 1995 vol. 36 no. 6 1183-1187参照）。 The chick is known to be short-sighted in about one week when one eye is covered with a transparent hemisphere, and is used as a model for myopic progression (for example, Seko et al., Invest Ophthalmol. Vis. Sci. May 1995 vol. 36 no. 6 1183-1187).
生後２日目のヒヨコ（ホワイトレグホン種）合計２３羽を片眼遮蔽し、以下の４群にわけた。なお、メトホルミンとして、メトホルミン塩酸塩である1,1-Dimethylbiguanide hydrochloride （Sigma-Aldrich社)を用いた。なお、投与量はニワトリでのメトホルミン経口投与の既報（Ashwell C.M, et al. Poult Sci, 2003）で300-600mg/kg/dayの投与をしており、その投与量を参考とした。
（Ａ）薬剤投与無し（５羽、以下投与無し群）
（Ｂ）メトホルミン250 mg/kg/日、７日間連続投与（６羽、以下250 mg/kg/日投与群）
（Ｃ）メトホルミン500 mg/kg/日、７日間連続投与（６羽、以下500 mg/kg/日投与群）
（Ｄ）メトホルミン1000mg/kg/日、７日間連続投与（６羽、以下1000mg/kg/日投与群）
片眼遮蔽のまま１週間、上記条件で飼育後、ヒヨコの眼球を摘出しノギスで全眼球長を測定した。結果の平均値を表１に示す。なお、硝子体腔長および眼軸長も測定し、それらの平均値を表２に示す。なお、統計処理には、Tukey HSD検定を用いた。 A total of 23 chicks (White Leghorn species) on the second day after birth were shielded with one eye and divided into the following 4 groups. 1,1-Dimethylbiguanide hydrochloride (Sigma-Aldrich), which is metformin hydrochloride, was used as metformin. In addition, the dosage was 300-600 mg / kg / day administered in the previous report of oral administration of metformin in chicken (Ashwell CM, et al. Poult Sci, 2003), and the dosage was referred to.
(A) No drug administration (five, no administration group below)
(B) Metformin 250 mg / kg / day, continuous administration for 7 days (6 animals, 250 mg / kg / day administration group)
(C) Metformin 500 mg / kg / day, continuous administration for 7 days (6 birds, 500 mg / kg / day administration group)
(D) Metformin 1000 mg / kg / day, continuous administration for 7 days (6 birds, 1000 mg / kg / day administration group)
After keeping for one week with one eye occlusion under the above conditions, the chick's eyeball was removed and the total eyeball length was measured with calipers. The average result is shown in Table 1. The vitreous cavity length and the axial length were also measured, and the average values are shown in Table 2. The Tukey HSD test was used for statistical processing.
その結果、平均全眼球長は、遮蔽眼では、投与無し群と比べて他の全ての投与群には有意な（p<0.05）眼球長伸長抑制効果があった。また、非遮蔽眼でもそれぞれ9.68mm, 9.17mm, 9.17mm, 8.98mmとなり、投与無し群と比べ、250 mg/kg/日投与群及び500 mg/kg/日投与群では、眼球長伸長抑制傾向にあり、1000mg/kg/day投与群では有意に（p<0.05）眼球長伸長抑制効果があった。一方、硝子体腔長および眼軸長は、投与群と投与無し群では有意差を認めなかったが、硝子体腔長・眼軸長伸長抑制の可能性がある。
＜実施例２＞As a result, the average total ocular length was significantly (p <0.05) less effective in suppressing ocular length in all other administration groups compared to the non-administration group in shielded eyes. In addition, the non-shielded eyes were 9.68 mm, 9.17 mm, 9.17 mm, and 8.98 mm, respectively, and compared to the non-administered group, there was a tendency to suppress eye length elongation in the 250 mg / kg / day and 500 mg / kg / day groups. 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 of suppressing the elongation of the vitreous cavity length and the axial length.
<Example 2>
生後２日目のヒヨコ（ホワイトレグホン種）合計１７羽を片眼遮蔽して生後５日目まで飼育し、以下の２群にわけた。なお、メトホルミンは実施例１と同じものを用いた。
（Ａ）生理食塩水投与、薬剤投与無し（８羽、以下投与無し群）
（Ｂ）メトホルミン（500 mg/kg/日）含有生理食塩水を、６日目から毎朝連続投与（９羽、以下500 mg/kg/日投与群）
片眼遮蔽のまま７日間、上記条件で飼育後、ヒヨコの眼球を摘出し、ノギスで硝子体腔長および眼軸長を測定し、B-mode解析を行った。それらの結果をそれぞれ図１及び図２に示す。なお、統計処理には、Mann-Whitney U testを用いた。A total of 17 chicks (white leghorn species) on the second day after birth were shielded with one eye and bred until the fifth day after birth, and divided into the following two groups. Metformin was the same as that used in Example 1.
(A) Saline administration, no drug administration (eight, no administration group below)
(B) Metformin (500 mg / kg / day) -containing physiological saline continuously administered every morning from the sixth day (9 birds, 500 mg / kg / day administration group)
After breeding under the above conditions for 7 days with one eye occlusion, the eyeballs of the chick 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. In addition, Mann-Whitney U test was used for statistical processing.
その結果、図１及び図２に示すように、硝子体腔長は、遮蔽眼では非遮蔽眼と比べて有意に（p<0.05）伸長した。そして、遮蔽眼でも非遮蔽眼も、メトホルミンには有意な硝子体腔長及び眼軸長伸長抑制効果があった。
＜結論＞
このように、メトホルミンは、眼球長伸長抑制効果を有し、近視予防剤及び近視進行抑制剤として有効である。As a result, as shown in FIGS. 1 and 2, the vitreous cavity length significantly increased (p <0.05) in the shielded eye compared to the non-shielded eye. In both shielded and non-shielded eyes, metformin had significant effects of suppressing the vitreous cavity length and axial length elongation.
<Conclusion>
Thus, metformin has an effect of suppressing eyeball length elongation and is effective as a myopia preventive agent and a myopia progression inhibitor.
すなわち、メトホルミン、ブホルミン、フェンホルミンを含む、下記構造式を有する化合物またはその薬学的に受容できる塩は、近視予防剤及び近視進行抑制剤として有効である。 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 preventing agent and a myopia progression inhibitor.
（式中、Ｒ１及びＲ２は、水素、及びフェニル置換してもよいＣ１−６アルキル基から独立して選択される基である。）
また、メトホルミンは、硝子体腔長伸長抑制効果及び眼軸長伸長抑制効果も有する。(In the formula, R 1 and R 2 are groups independently selected from hydrogen and a C 1-6 alkyl group which may be phenyl-substituted.)
Metformin also has a vitreous cavity length elongation inhibitory effect and an ocular axial length elongation inhibitory effect.
本発明によって、近視予防剤及び近視進行抑制剤を提供することができるようになった。 According to the present invention, a myopia preventive agent and a myopia progression inhibitor can be provided.
Claims (12)
A method for screening for a myopia preventive or a myopia progression inhibitor, comprising the step of administering to a chick a compound having the following structural formula or a pharmaceutically acceptable salt thereof, the total eye length of the chick, the vitreous cavity length, Or measuring the axial length and obtaining a first measurement result; and determining the first measurement result from the total eyeball length, vitreous cavity length, or eye axis of a control chick not administered with the compound or its salt A step of comparing with a second measurement result obtained by measuring the length, a step of specifying a compound or a salt thereof whose first measurement result is significantly shorter than the second measurement result, and the specified compound Or a step of using a salt thereof as a myopia preventive or a myopia progression inhibitor.
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