WO2020230251A1 - Therapeutic agent for retinal diseases - Google Patents

Therapeutic agent for retinal diseases Download PDF

Info

Publication number
WO2020230251A1
WO2020230251A1 PCT/JP2019/019009 JP2019019009W WO2020230251A1 WO 2020230251 A1 WO2020230251 A1 WO 2020230251A1 JP 2019019009 W JP2019019009 W JP 2019019009W WO 2020230251 A1 WO2020230251 A1 WO 2020230251A1
Authority
WO
WIPO (PCT)
Prior art keywords
therapeutic agent
day
age
amd
ipragliflozin
Prior art date
Application number
PCT/JP2019/019009
Other languages
French (fr)
Japanese (ja)
Inventor
登與志 井口
真由実 大和
Original Assignee
株式会社カルナヘルスサポート
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 株式会社カルナヘルスサポート filed Critical 株式会社カルナヘルスサポート
Priority to PCT/JP2019/019009 priority Critical patent/WO2020230251A1/en
Publication of WO2020230251A1 publication Critical patent/WO2020230251A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to a therapeutic agent for treating a retinal disease.
  • Age-related macular degeneration which is one of the retinal diseases, is the number one cause of blindness in adults in Europe and the United States, and the number four in Japan. In the future, it is expected that the number of patients with age-related macular degeneration will increase around the world as the population ages. Although the decrease in visual acuity caused by this disease causes a significant decrease in QOL of many patients, there is currently no effective treatment method.
  • SGLT2 inhibitors inhibit sodium / glucose co-transporter 2 (sodium / glucose co-transporter2: SGLT2), which is specifically present in the proximal tubules of the kidney and is reabsorbing glucose, and urine. It is an antidiabetic agent that exhibits a hypoglycemic effect by promoting glucose excretion from the body, and six SGLT2 inhibitors have already been clinically applied (see, for example, Non-Patent Documents 1 and 2). However, it is not known that this SGLT2 inhibitor has a direct improving effect on retinal diseases not caused by hyperglycemia such as age-related macular degeneration.
  • An object of the present invention is to provide a therapeutic agent for treating and / or ameliorating a retinal disease such as age-related macular degeneration.
  • the present inventors In studying the action and effect of an SGLT2 inhibitor as an antidiabetic agent exhibiting a hypoglycemic effect, the present inventors first, first, proximal to the action of the SGLT2 inhibitor with respect to the actual dose of the SGLT2 inhibitor. Focusing on the fact that only a very small amount reaches the tubules, glucose-induced retinopathy (at low doses where existing SGLT2 inhibitors do not show hypoglycemic effects and those that do not. It was found that it exerts an improving effect on (retinopathy caused by hyperglycemia) (PCT / JP2016 / 86658).
  • an SGLT2 inhibitor also exhibits a protective effect in an age-related macular degeneration model mouse that does not show hyperglycemia. That is, uptake of sodium and / or glucose also for age-related macular degeneration, which is a completely different disease (retinal disease not caused by hyperglycemia) that is not caused by excessive influx of glucose into retinal constituent cells due to hyperglycemia.
  • a mechanism such as suppression we have found that an improvement effect is exhibited by a mechanism such as suppression, and have completed the present invention.
  • a therapeutic agent for retinal diseases not caused by hyperglycemia which comprises a sodium / glucose cotransporter 2 inhibitor (SGLT2 inhibitor) which is a phlorizin derivative as an active ingredient.
  • the therapeutic agent according to the above [1] which is used so as to be administered at a low dose in which hypoglycemia is not observed.
  • the SGLT2 inhibitor is at least one selected from canagliflozin, ipragliflozin, dapagliflozin, luseogliflozin, empagliflozin, tofogliflozin and ertzgliflozin, as described above [1] or [ 2] The therapeutic agent described.
  • the therapeutic agent according to any one of the above [1] to [3], wherein the retinal disease not caused by hyperglycemia is age-related macular degeneration.
  • a low-dose SGLT2 inhibitor having a hypoglycemic dose and a lower hypoglycemic effect is not caused by hyperglycemia such as age-related macular degeneration.
  • the therapeutic agent of the present invention is effective when administered at a low dose, hypoglycemia, polyuria / pollakiuria, dehydration, and urinary tract are the main side effects caused by the urinary glucose excretion promoting action of existing SGLT2 inhibitors.
  • There are no problems such as infectious diseases, genital infections, and increase in ketone bodies, and the safety is extremely high.
  • the therapeutic agent of the present invention enables new indication expansion as a therapeutic agent for age-related macular degeneration and the like.
  • AMD represents an age-related macular degeneration model mouse that has been bred for one week after light irradiation (8000 lux, 10 hours).
  • AMD represents an age-related macular degeneration model mouse that has been bred for one week after light irradiation (8000 lux, 10 hours).
  • FIG. 1 It is a figure which shows the hematoxylin-eosin staining of the retina of the age-related macular degeneration model mouse which administered ipragliflozin.
  • Control represents a control mouse
  • AMD represents an age-related macular degeneration model mouse that has been bred for one week after light irradiation (8000 lux, 10 hours).
  • Ipra. (0.03) represents AMD mice administered with ipragliflozin 0.03 mg / kg / day
  • Ipra. (0.1) represents ipragliflozin 0.1 mg / kg / day. Represents an AMD mouse.
  • “***” represents P ⁇ 0.005 vs control mouse, and “#” and “##” are P ⁇ 0.05 vs ipragliflozin-free AMD mouse and P ⁇ 0.01 vs i, respectively.
  • Control represents a control mouse
  • AMD age-related macular degeneration model mouse that has been bred for one week after light irradiation (8000 lux, 10 hours).
  • Luse. (0.03) represents AMD mice administered with luseogliflozin 0.03 mg / kg / day
  • Luse. (0.1) represents luseogliflozin 0.1 mg / kg / day.
  • *** represents P ⁇ 0.005 vs. control mouse, and “#” represents P ⁇ 0.05 vs. Luceogliflozin-free AMD mouse.
  • Represents an AMD mouse (n 3) administered with tofogliflozin 0.1 mg / kg / day.
  • “***” represents P ⁇ 0.005 vs. control mouse
  • “####” represents P ⁇ 0.005 vs tofogliflozin-free AMD mouse. It is a figure which quantified the thickness of the outer nuclear layer (including photoreceptor cells) of the retina of the age-related macular degeneration model mouse to which canagliflozin was administered.
  • *** represents P ⁇ 0.005 vs. control mouse
  • #### represents P ⁇ 0.005 vs canagliflozin-free AMD mouse.
  • the therapeutic agent of the present invention is a therapeutic agent for retinal diseases not caused by hyperglycemia, and contains an SGLT2 inhibitor which is a phlorizin derivative as an active ingredient.
  • the present invention has a retinal protective effect of an SGLT2 inhibitor at a dose at which hypoglycemic activity is observed and at a low dose at which a lower hypoglycemic effect is not observed, by a mechanism completely different from that of tubular SGLT2 inhibition.
  • an SGLT2 inhibitor exhibits retinal function protection (visual function protection effect) by suppressing the uptake of sodium and / or glucose into the intracellular constituent cells of the retina.
  • the therapeutic agent of the present invention it is considered that even in retinal disorders not caused by hyperglycemia, the uptake of sodium and / or glucose into the intracellular constituent cells of the retina is suppressed and the retinal function is improved.
  • SGLT2 inhibitors showed an ameliorating effect on retinal damage in age-related macular degeneration model mice.
  • the retinal disease to which the therapeutic agent of the present invention is targeted is not particularly limited as long as it is a retinal disease not caused by hyperglycemia.
  • the retina is damaged for some reason, the visual field is narrowed, or the visual acuity is impaired. Diseases that decrease can be mentioned.
  • Specific examples thereof include age-related macular degeneration and retinitis pigmentosa, in which the macula, which is the central part of the retina, is damaged by aging.
  • the SGLT2 inhibitor in the therapeutic agent of the present invention is particularly limited as long as it is a phlorizin derivative that binds to SGLT2 and exhibits an antagonistic inhibitory effect on sodium and / or glucose uptake via SGLT2. is not.
  • SGLT2 inhibitors examples include canagliflozin, ipragliflozin, dapagliflozin, luseogliflozin, empagliflozin, tofogliflozin, and ertugliflozin, and specifically, the active ingredient of an existing SGLT2 inhibitor.
  • Canaglyflozin hydrate (C 24 H 25 FO 5 S ⁇ 1 / 2H 2 O), ipragliflozin L-proline (C 21 H 21 FO 5 S ⁇ C 5 H 9 NO 2 ), Dapa Glyflozin propylene glycol hydrate (C 21 H 25 ClO 6 ⁇ C 3 H 8 O 2 ⁇ H 2 O), Luceogliflozin hydrate (C 23 H 30 O 6 S ⁇ xH 2 O), empagliflozin (C 23 H 27 ClO 7 ), tofogliflozin hydrate (C 22 H 26 O 6 ⁇ H 2 O), eltzgliflozin pidroate (C 22 H 25 ClO 7 ⁇ C 5 H 7 NO 3 ), etc. Can be exemplified.
  • canagliflozin means a substance having the following canagliflozin structure, which is a pharmaceutically acceptable hydrate, alcohol adduct, or amino acid. It contains adducts, salts, etc. The same applies to other SGLT2 inhibitors such as "ipragliflozin”.
  • the dose of the therapeutic agent of the present invention may be a dose at which hypoglycemic action is observed, or a low dose at which a lower hypoglycemic effect is not observed. That is, the therapeutic agent of the present invention reaches an effective concentration that inhibits SGLT2 of retinal constituent cells such as photoreceptor cells in blood or retinal tissue even at a low dose that does not reach the effective concentration in urine that suppresses SGLT2, and retinal function. It acts protectively.
  • the low dose at which the hypoglycemic effect is not observed is an amount that does not significantly lower blood glucose, and for example, in the case of the active ingredient of a hypoglycemic agent for which an SGLT2 inhibitor is approved, the approved minimum amount. Means a dose less than the dose.
  • the lower limit may be appropriately determined within the range in which the effect is exhibited.
  • canagliflozin hydrate is about 1/100 of the approved minimum dose.
  • Ipragliflozin L-proline has a maximum blood concentration (Cmax) similar to that of canagliflozin at the minimum dose, and an IC50 value showing inhibitory activity is also similar. It is about / 100.
  • the maximum blood concentration (Cmax) at the minimum dose is about 1/10 of canagliflozin. Since the IC50 values are similar, they are about 1/10.
  • the canagliflozin hydrate approved as a hypoglycemic agent is less than 100 mg (as canagliflozin) per adult per day, may be 90 mg or less, or may be 70 mg or less. , 50 mg or less, 30 mg or less, 10 mg or less, 5 mg or less, and the lower limit thereof is about 1 mg.
  • Ipragliflozin L-proline is less than 50 mg per day (as ipragliflozin) for adults, may be 40 mg or less, 30 mg or less, 20 mg or less, or 10 mg or less. It may be 5 mg or less, or 1 mg or less, and the lower limit thereof is about 0.5 mg.
  • Dapagliflozin propylene glycol hydrate is less than 5 mg per day (as dapagliflozin) for adults, may be 4 mg or less, 3 mg or less, 2 mg or less, or 1 mg or less. It may be present, and the lower limit thereof is about 0.5 mg.
  • Luceogliflozin hydrate is less than 2.5 mg (as luseogliflozin) per day for adults, may be 2 mg or less, 1.5 mg or less, or 1 mg or less. It may be 0.5 mg or less, and the lower limit thereof is about 0.25 mg.
  • Empagliflozin is less than 10 mg per day for adults, may be 9 mg or less, 6 mg or less, 4 mg or less, 2 mg or less, and the lower limit is 0. It is about 1 mg.
  • the daily adult is less than 20 mg, may be 18 mg or less, 15 mg or less, 10 mg or less, 5 mg or less, and may be.
  • the lower limit is about 2 mg.
  • Examples of the administration form of the therapeutic agent of the present invention include oral use, injection use, etc., but it is preferably oral use as in the existing SGLT2 inhibitor (hypoglycemic agent).
  • examples of the form of the therapeutic agent of the present invention include various forms such as tablets, granules, powders, capsules, and liquids.
  • the therapeutic agent of the present invention containing an SGLT2 inhibitor as an active ingredient is found to have a hypoglycemic dose or a hypoglycemic dose.
  • the method is not particularly limited as long as it is administered to a patient at a non-dose dose, and as described above, oral administration, injection administration and the like can be exemplified as the administration method. Details of the therapeutic agent of the present invention, its dose, specific examples of the retinal disease to be treated, and the like are as described above.
  • mice were irradiated with light (8000 lux, 10 hours) and then bred for 1 week.
  • the existing SGLT2 inhibitor ipragliflozin was orally administered at 0.03 mg / kg / day and 0.1 mg / kg / day for 4 days including the day of light irradiation, and the effect on body weight and blood glucose was confirmed.
  • This model is widely used as an age-related macular degeneration model.
  • FIGS. 1 and 2 show the results of body weight and blood glucose levels when the existing SGLT2 inhibitor ipragliflozin 0.03 mg / kg / day and 0.1 mg / kg / day were administered. As shown in FIGS. 1 and 2, no change was observed in body weight and blood glucose at any dose as compared with the case where ipragliflozin was not administered. As with body weight and blood glucose, no change was observed in urinary sugar as compared with the case where ipragliflozin was not administered.
  • Example 1 Hematoxylin and eosin staining confirmed the protective effect of ipragliflozin on the retina at low doses (0.03 mg / kg / day and 0.1 mg / kg / day) without hypoglycemia.
  • the administration period of ipragliflozin is 4 days including the day of light irradiation, as in the preliminary test.
  • FIG. 4 shows the thickness of the outer nuclear layer (including photoreceptor cells) of the retina measured and quantified.
  • ipragliflozin 0.03 mg / kg / day and 0.1 mg / kg / day are doses that do not show hypoglycemia, but as shown in FIGS. 3 and 4, they are not shown.
  • Administration of ipragliflozin 0.03 mg / kg / day and 0.1 mg / kg / day showed a significant improvement in membrane thinning seen in the retina of AMD mice.
  • the retinal pigment epithelium gradually atrophies, the retina is damaged and the visual acuity gradually deteriorates. It is expected that the visual function will be improved.
  • Example 2 Hematoxylin and eosin staining confirmed the protective effect of luseogliflozin on the retina at low doses (0.03 mg / kg / day and 0.1 mg / kg / day) without hypoglycemia.
  • the administration period of luseogliflozin is 4 days including the day of light irradiation.
  • FIGS. 5 and 6 show the thickness of the outer nuclear layer (including photoreceptor cells) of the retina measured and quantified.
  • Example 3 Hematoxylin and eosin staining confirmed the protective effect of tofogliflozin on the retina at low doses (0.03 mg / kg / day and 0.1 mg / kg / day) without hypoglycemia.
  • the administration period of tofogliflozin is 4 days including the day of light irradiation.
  • FIG. 7 shows the thickness of the outer nuclear layer (including photoreceptor cells) of the retina measured and quantified.
  • Example 4 Hematoxylin and eosin staining confirmed the protective effect of canagliflozin on the retina at low doses (0.03 mg / kg / day and 0.1 mg / kg / day) without hypoglycemia.
  • the administration period of canagliflozin is 4 days including the day of light irradiation.
  • the result is shown in FIG. FIG. 8 shows the thickness of the outer nuclear layer (including photoreceptor cells) of the retina measured and quantified.
  • the therapeutic agent of the present invention has an effect of improving age-related macular degeneration at a dose that does not cause hypoglycemia.
  • the therapeutic agent of the present invention enables new indications to be expanded as a therapeutic agent for age-related macular degeneration and the like, and is highly industrially useful.

Abstract

This therapeutic agent for retinal diseases such as age-related macular degeneration contains, as an active ingredient, a sodium/glucose cotransporter 2 (SGLT2) inhibitory substance which is a phlorizin derivative such as canagliflozin, ipragliflozin, dapagliflozin, luseogliflozin, empagliflozin, tofogliflozin and ertugliflozin.

Description

網膜疾患治療剤Retinal disease therapeutic agent
　本発明は、網膜疾患を治療する治療剤に関する。 The present invention relates to a therapeutic agent for treating a retinal disease.
　網膜疾患の１つである加齢黄斑変性症は、欧米では成人の失明原因の第１位、日本では第４位の病気である。今後、高齢化進展にともない、世界中で加齢黄斑変性症の患者数が増加していくと考えられている。本疾患による視力低下は、多くの患者のＱＯＬを著しく低下させる原因となっているが、未だ有効な治療法はないのが現状である。 Age-related macular degeneration, which is one of the retinal diseases, is the number one cause of blindness in adults in Europe and the United States, and the number four in Japan. In the future, it is expected that the number of patients with age-related macular degeneration will increase around the world as the population ages. Although the decrease in visual acuity caused by this disease causes a significant decrease in QOL of many patients, there is currently no effective treatment method.
　また、加齢黄斑変性症の進展増悪の抑制や改善をする経口治療薬は、現在存在しておらず、その開発が強く望まれている。 In addition, there is currently no oral therapeutic agent that suppresses or ameliorate the progression and exacerbation of age-related macular degeneration, and its development is strongly desired.
　一方、ＳＧＬＴ２阻害薬は、腎近位尿細管に特異的に存在し、グルコースの再吸収を行っているナトリウム／グルコース共輸送体２（ｓｏｄｉｕｍ／ｇｌｕｃｏｓｅ ｃｏ－ｔｒａｎｓｐｏｒｔｅｒ２：ＳＧＬＴ２）を阻害して、尿からのグルコース排泄を促進することにより血糖降下作用を示す糖尿病治療薬であり、既に６種のＳＧＬＴ２阻害薬の臨床応用が行われている（例えば、非特許文献１，２参照）。しかしながら、このＳＧＬＴ２阻害薬が、加齢黄斑変性症などの高血糖に起因しない網膜疾患に対して直接的改善効果を有することは知られていない。 On the other hand, SGLT2 inhibitors inhibit sodium / glucose co-transporter 2 (sodium / glucose co-transporter2: SGLT2), which is specifically present in the proximal tubules of the kidney and is reabsorbing glucose, and urine. It is an antidiabetic agent that exhibits a hypoglycemic effect by promoting glucose excretion from the body, and six SGLT2 inhibitors have already been clinically applied (see, for example, Non-Patent Documents 1 and 2). However, it is not known that this SGLT2 inhibitor has a direct improving effect on retinal diseases not caused by hyperglycemia such as age-related macular degeneration.
　本発明の課題は、加齢黄斑変性症等の網膜疾患を治療及び／又は改善する治療剤を提供することにある。 An object of the present invention is to provide a therapeutic agent for treating and / or ameliorating a retinal disease such as age-related macular degeneration.
　本発明者らは、血糖降下作用を示す糖尿病治療薬としてのＳＧＬＴ２阻害薬の作用効果について研究する中で、まず、ＳＧＬＴ２阻害薬の実際の投与量に対して、ＳＧＬＴ２阻害薬が作用する近位尿細管にはごく少量しか届いていないことに着目し、既存のＳＧＬＴ２阻害薬が、血糖降下作用を示す投与量及び血糖降下作用を示さないような低用量投与において、グルコースに起因する網膜症（高血糖に起因する網膜症）に対する改善効果を発揮することを見いだした（ＰＣＴ／ＪＰ２０１６／８６６５８）。 In studying the action and effect of an SGLT2 inhibitor as an antidiabetic agent exhibiting a hypoglycemic effect, the present inventors first, first, proximal to the action of the SGLT2 inhibitor with respect to the actual dose of the SGLT2 inhibitor. Focusing on the fact that only a very small amount reaches the tubules, glucose-induced retinopathy (at low doses where existing SGLT2 inhibitors do not show hypoglycemic effects and those that do not. It was found that it exerts an improving effect on (retinopathy caused by hyperglycemia) (PCT / JP2016 / 86658).
　本発明者らは、さらに研究を進めた結果、ＳＧＬＴ２阻害薬が、高血糖を示さない加齢黄斑変性症モデルマウスにおいても保護効果を示すことを見出した。すなわち、高血糖による網膜構成細胞内へのグルコースの過剰流入に起因しない全く別の疾患（高血糖に起因しない網膜疾患）である加齢黄斑変性症に対しても、ナトリウム及び／又はグルコースの取り込み抑制といった機序で、改善効果を発揮することを見いだし、本発明を完成するに至った。 As a result of further research, the present inventors have found that an SGLT2 inhibitor also exhibits a protective effect in an age-related macular degeneration model mouse that does not show hyperglycemia. That is, uptake of sodium and / or glucose also for age-related macular degeneration, which is a completely different disease (retinal disease not caused by hyperglycemia) that is not caused by excessive influx of glucose into retinal constituent cells due to hyperglycemia. We have found that an improvement effect is exhibited by a mechanism such as suppression, and have completed the present invention.
　すなわち、本発明は、以下のとおりのものである。
　［１］フロリジン誘導体であるナトリウム／グルコース共輸送体２阻害物質（ＳＧＬＴ２阻害物質）を有効成分とすることを特徴とする高血糖に起因しない網膜疾患の治療剤。
　［２］血糖降下が認められない低用量で投与されるよう用いられることを特徴とする上記［１］記載の治療剤。
　［３］ＳＧＬＴ２阻害物質が、カナグリフロジン、イプラグリフロジン、ダパグリフロジン、ルセオグリフロジン、エンパグリフロジン、トホグリフロジン及びエルツグリフロジンから選ばれる少なくとも１種であることを特徴とする上記［１］又は［２］記載の治療剤。
　［４］高血糖に起因しない網膜疾患が、加齢黄斑変性症であることを特徴とする上記［１］～［３］のいずれか記載の治療剤。 That is, the present invention is as follows.
[1] A therapeutic agent for retinal diseases not caused by hyperglycemia, which comprises a sodium / glucose cotransporter 2 inhibitor (SGLT2 inhibitor) which is a phlorizin derivative as an active ingredient.
[2] The therapeutic agent according to the above [1], which is used so as to be administered at a low dose in which hypoglycemia is not observed.
[3] The SGLT2 inhibitor is at least one selected from canagliflozin, ipragliflozin, dapagliflozin, luseogliflozin, empagliflozin, tofogliflozin and ertzgliflozin, as described above [1] or [ 2] The therapeutic agent described.
[4] The therapeutic agent according to any one of the above [1] to [3], wherein the retinal disease not caused by hyperglycemia is age-related macular degeneration.
　本発明の治療剤によれば、血糖降下が認められる投与量、及びそれより少ない血糖降下作用が認められない低用量のＳＧＬＴ２阻害薬の投与で、加齢黄斑変性症等の高血糖に起因しない網膜疾患を治療することができる。本発明の治療剤は、低用量の投与で効果が表れることから、既存のＳＧＬＴ２阻害薬の尿糖排泄促進作用に起因する主な副作用である低血糖、多尿・頻尿、脱水、尿路感染症・性器感染症、ケトン体の増加といった問題がなく、また安全性も極めて高い。本発明の治療剤は、加齢黄斑変性症等の治療薬としての新たな適応拡大を可能とするものである。 According to the therapeutic agent of the present invention, administration of a low-dose SGLT2 inhibitor having a hypoglycemic dose and a lower hypoglycemic effect is not caused by hyperglycemia such as age-related macular degeneration. Can treat retinal disorders. Since the therapeutic agent of the present invention is effective when administered at a low dose, hypoglycemia, polyuria / pollakiuria, dehydration, and urinary tract are the main side effects caused by the urinary glucose excretion promoting action of existing SGLT2 inhibitors. There are no problems such as infectious diseases, genital infections, and increase in ketone bodies, and the safety is extremely high. The therapeutic agent of the present invention enables new indication expansion as a therapeutic agent for age-related macular degeneration and the like.
加齢黄斑変性症モデルマウスの体重に対するイプラグリフロジン投与の効果を示す図である。「ｃｏｎｔｒｏｌ」は、対照マウス（ｎ＝９）を表し、「ＡＭＤ」は、光照射後（８０００ｌｕｘ、１０時間）、一週間飼育した加齢黄斑変性症モデルマウスを表す。「０」は、イプラグリフロジン非投与のＡＭＤマウス（ｎ＝９）を表し、「０．０３」は、イプラグリフロジン０．０３ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝９）を表し、「０．１」は、イプラグリフロジン０．１ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝９）を表す。It is a figure which shows the effect of ipragliflozin administration on the body weight of the age-related macular degeneration model mouse. "Control" represents a control mouse (n = 9), and "AMD" represents an age-related macular degeneration model mouse that has been bred for one week after light irradiation (8000 lux, 10 hours). “0” represents an AMD mouse (n = 9) not administered with ipragliflozin, and “0.03” represents an AMD mouse (n = 9) administered with ipragliflozin 0.03 mg / kg / day. “0.1” represents AMD mice (n = 9) administered with ipragliflozin 0.1 mg / kg / day. 加齢黄斑変性症モデルマウスの血糖に対するイプラグリフロジン投与の効果を示す図である。「ｃｏｎｔｒｏｌ」は、対照マウス（ｎ＝９）を表し、「ＡＭＤ」は、光照射後（８０００ｌｕｘ、１０時間）、一週間飼育した加齢黄斑変性症モデルマウスを表す。「０」は、イプラグリフロジン非投与のＡＭＤマウス（ｎ＝９）を表し、「０．０３」は、イプラグリフロジン０．０３ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝９）を表し、「０．１」は、イプラグリフロジン０．１ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝９）を表す。It is a figure which shows the effect of ipragliflozin administration on the blood glucose of the age-related macular degeneration model mouse. "Control" represents a control mouse (n = 9), and "AMD" represents an age-related macular degeneration model mouse that has been bred for one week after light irradiation (8000 lux, 10 hours). “0” represents an AMD mouse (n = 9) not administered with ipragliflozin, and “0.03” represents an AMD mouse (n = 9) administered with ipragliflozin 0.03 mg / kg / day. “0.1” represents AMD mice (n = 9) administered with ipragliflozin 0.1 mg / kg / day. イプラグリフロジンを投与した加齢黄斑変性症モデルマウスの網膜のヘマトキシリン・エオジン染色を示す図である。「ｃｏｎｔｒｏｌ」は、対照マウスを表し、「ＡＭＤ」は、光照射後（８０００ｌｕｘ、１０時間）、一週間飼育した加齢黄斑変性症モデルマウスを表す。「Ｉｐｒａ．（０．０３）」は、イプラグリフロジン０．０３ｍｇ／ｋｇ／日投与のＡＭＤマウスを表し、「Ｉｐｒａ．（０．１）」は、イプラグリフロジン０．１ｍｇ／ｋｇ／日投与のＡＭＤマウスを表す。It is a figure which shows the hematoxylin-eosin staining of the retina of the age-related macular degeneration model mouse which administered ipragliflozin. "Control" represents a control mouse, and "AMD" represents an age-related macular degeneration model mouse that has been bred for one week after light irradiation (8000 lux, 10 hours). "Ipra. (0.03)" represents AMD mice administered with ipragliflozin 0.03 mg / kg / day, and "Ipra. (0.1)" represents ipragliflozin 0.1 mg / kg / day. Represents an AMD mouse. イプラグリフロジンを投与した加齢黄斑変性症モデルマウスの網膜の外顆粒層（視細胞を含む）の厚さを数値化した図である。「ｃｏｎｔｒｏｌ」は、対照マウス（ｎ＝３）を表し、「ＡＭＤ」は、光照射後（８０００ｌｕｘ、１０時間）、一週間飼育した加齢黄斑変性症モデルマウス（ｎ＝３）を表す。「０」は、イプラグリフロジン非投与のＡＭＤマウス（ｎ＝３）を表し、「０．０３」は、イプラグリフロジン０．０３ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝３）を表し、「０．１」は、イプラグリフロジン０．１ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝３）を表す。「＊＊＊」は、Ｐ＜０．００５ ｖｓ対照マウスを表し、「＃」及び「＃＃」は、それぞれ、Ｐ＜０．０５ｖｓイプラグリフロジン非投与ＡＭＤマウス、及びＰ＜０．０１ｖｓ イプラグリフロジン非投与ＡＭＤマウスを表す。It is a figure which quantified the thickness of the outer nuclear layer (including photoreceptor cells) of the retina of the age-related macular degeneration model mouse to which ipragliflozin was administered. “Control” represents a control mouse (n = 3), and “AMD” represents an age-related macular degeneration model mouse (n = 3) that was bred for one week after light irradiation (8000 lux, 10 hours). “0” represents an AMD mouse (n = 3) not administered with ipragliflozin, and “0.03” represents an AMD mouse (n = 3) administered with ipragliflozin 0.03 mg / kg / day. “0.1” represents AMD mice (n = 3) administered with ipragliflozin 0.1 mg / kg / day. “***” represents P <0.005 vs control mouse, and “#” and “##” are P <0.05 vs ipragliflozin-free AMD mouse and P <0.01 vs i, respectively. Represents a plugriflozin-free AMD mouse. ルセオグリフロジンを投与した加齢黄斑変性症モデルマウスの網膜のヘマトキシリン・エオジン染色を示す図である。「ｃｏｎｔｒｏｌ」は、対照マウスを表し、「ＡＭＤ」は、光照射後（８０００ｌｕｘ、１０時間）、一週間飼育した加齢黄斑変性症モデルマウスを表す。「Ｌｕｓｅ．（０．０３）」は、ルセオグリフロジン０．０３ｍｇ／ｋｇ／日投与のＡＭＤマウスを表し、「Ｌｕｓｅ．（０．１）」は、ルセオグリフロジン０．１ｍｇ／ｋｇ／日投与のＡＭＤマウスを表す。It is a figure which shows the hematoxylin and eosin staining of the retina of the age-related macular degeneration model mouse to which Luceogliflozin was administered. "Control" represents a control mouse, and "AMD" represents an age-related macular degeneration model mouse that has been bred for one week after light irradiation (8000 lux, 10 hours). "Luse. (0.03)" represents AMD mice administered with luseogliflozin 0.03 mg / kg / day, and "Luse. (0.1)" represents luseogliflozin 0.1 mg / kg / day. Represents an AMD mouse. ルセオグリフロジンを投与した加齢黄斑変性症モデルマウスの網膜の外顆粒層（視細胞を含む）の厚さを数値化した図である。「ｃｏｎｔｒｏｌ」は、対照マウス（ｎ＝３）を表し、「ＡＭＤ」は、光照射後（８０００ｌｕｘ、１０時間）、一週間飼育した加齢黄斑変性症モデルマウス（ｎ＝３）を表す。「０」は、ルセオグリフロジン非投与のＡＭＤマウス（ｎ＝３）を表し、「０．０３」は、ルセオグリフロジン０．０３ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝３）を表し、「０．１」は、ルセオグリフロジン０．１ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝３）を表す。「＊＊＊」は、Ｐ＜０．００５ ｖｓ対照マウスを表し、「＃」は、Ｐ＜０．０５ｖｓルセオグリフロジン非投与ＡＭＤマウスを表す。It is a figure which quantified the thickness of the outer nuclear layer (including photoreceptor cells) of the retina of the age-related macular degeneration model mouse to which Luceogliflozin was administered. “Control” represents a control mouse (n = 3), and “AMD” represents an age-related macular degeneration model mouse (n = 3) that was bred for one week after light irradiation (8000 lux, 10 hours). "0" represents AMD mice not administered with luseogliflozin (n = 3), and "0.03" represents AMD mice administered with luseogliflozin 0.03 mg / kg / day (n = 3). “0.1” represents AMD mice (n = 3) administered with Luceogliflozin 0.1 mg / kg / day. “***” represents P <0.005 vs. control mouse, and “#” represents P <0.05 vs. Luceogliflozin-free AMD mouse. トホグリフロジンを投与した加齢黄斑変性症モデルマウスの網膜の外顆粒層（視細胞を含む）の厚さを数値化した図である。「ｃｏｎｔｒｏｌ」は、対照マウス（ｎ＝３）を表し、「ＡＭＤ」は、光照射後（８０００ｌｕｘ、１０時間）、一週間飼育した加齢黄斑変性症モデルマウス（ｎ＝３）を表す。「０」は、トホグリフロジン非投与のＡＭＤマウス（ｎ＝３）を表し、「０．０３」は、トホグリフロジン０．０３ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝３）を表し、「０．１」は、トホグリフロジン０．１ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝３）を表す。「＊＊＊」は、Ｐ＜０．００５ ｖｓ対照マウスを表し、「＃＃＃」は、Ｐ＜０．００５ｖｓトホグリフロジン非投与ＡＭＤマウスを表す。It is a figure which quantified the thickness of the outer nuclear layer (including photoreceptor cells) of the retina of the age-related macular degeneration model mouse to which tofogliflozin was administered. “Control” represents a control mouse (n = 3), and “AMD” represents an age-related macular degeneration model mouse (n = 3) that was bred for one week after light irradiation (8000 lux, 10 hours). "0" represents an AMD mouse (n = 3) not administered with tofogliflozin, and "0.03" represents an AMD mouse (n = 3) administered with tofogliflozin 0.03 mg / kg / day, and "0.1". Represents an AMD mouse (n = 3) administered with tofogliflozin 0.1 mg / kg / day. “***” represents P <0.005 vs. control mouse, and “####” represents P <0.005 vs tofogliflozin-free AMD mouse. カナグリフロジンを投与した加齢黄斑変性症モデルマウスの網膜の外顆粒層（視細胞を含む）の厚さを数値化した図である。「ｃｏｎｔｒｏｌ」は、対照マウス（ｎ＝３）を表し、「ＡＭＤ」は、光照射後（８０００ｌｕｘ、１０時間）、一週間飼育した加齢黄斑変性症モデルマウス（ｎ＝３）を表す。「０」は、カナグリフロジン非投与のＡＭＤマウス（ｎ＝３）を表し、「０．０３」は、カナグリフロジン０．０３ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝３）を表し、「０．１」は、カナグリフロジン０．１ｍｇ／ｋｇ／日投与のＡＭＤマウス（ｎ＝３）を表す。「＊＊＊」は、Ｐ＜０．００５ ｖｓ対照マウスを表し、「＃＃＃」は、Ｐ＜０．００５ｖｓカナグリフロジン非投与ＡＭＤマウスを表す。It is a figure which quantified the thickness of the outer nuclear layer (including photoreceptor cells) of the retina of the age-related macular degeneration model mouse to which canagliflozin was administered. “Control” represents a control mouse (n = 3), and “AMD” represents an age-related macular degeneration model mouse (n = 3) that was bred for one week after light irradiation (8000 lux, 10 hours). “0” represents an AMD mouse (n = 3) not administered with canagliflozin, and “0.03” represents an AMD mouse (n = 3) administered with 0.03 mg / kg / day of canagliflozin. “0.1” represents AMD mice (n = 3) administered with canagliflozin 0.1 mg / kg / day. “***” represents P <0.005 vs. control mouse, and “####” represents P <0.005 vs canagliflozin-free AMD mouse.
　本発明の治療剤は、高血糖に起因しない網膜疾患の治療剤であって、フロリジン誘導体であるＳＧＬＴ２阻害物質を有効成分とする。 The therapeutic agent of the present invention is a therapeutic agent for retinal diseases not caused by hyperglycemia, and contains an SGLT2 inhibitor which is a phlorizin derivative as an active ingredient.
　本発明は、ＳＧＬＴ２阻害物質が、血糖降下が認められる投与量、及びそれより少ない血糖降下作用が認められない低用量において、尿細管ＳＧＬＴ２抑制とは全く異なった機序で、網膜保護効果をもつことを見出したものである。すなわち、本発明では、ＳＧＬＴ２阻害物質が、ナトリウム及び／又はグルコースの網膜構成細胞内への取り込みを抑制することで網膜機能保護（視覚機能保護作用）を示すことを見いだしたものである。 The present invention has a retinal protective effect of an SGLT2 inhibitor at a dose at which hypoglycemic activity is observed and at a low dose at which a lower hypoglycemic effect is not observed, by a mechanism completely different from that of tubular SGLT2 inhibition. I found that. That is, in the present invention, it has been found that an SGLT2 inhibitor exhibits retinal function protection (visual function protection effect) by suppressing the uptake of sodium and / or glucose into the intracellular constituent cells of the retina.
　本発明の治療剤によれば、高血糖に起因しない網膜障害においても、網膜構成細胞内へのナトリウム及び／又はグルコースの取り込みを抑制し、網膜機能を改善すると考えられる。実際、ＳＧＬＴ２阻害物質は、加齢黄斑変性症モデルマウスの網膜への障害に対する改善効果を示した。 According to the therapeutic agent of the present invention, it is considered that even in retinal disorders not caused by hyperglycemia, the uptake of sodium and / or glucose into the intracellular constituent cells of the retina is suppressed and the retinal function is improved. In fact, SGLT2 inhibitors showed an ameliorating effect on retinal damage in age-related macular degeneration model mice.
　本発明の治療剤の対象となる網膜疾患としては、高血糖に起因しない網膜疾患であれば特に制限されるものではなく、例えば、何らかの理由で網膜に障害が起こり、視野が狭くなったり視力が低下したりする疾患を挙げることができる。具体的には、加齢により網膜の中心部である黄斑に障害が生じる加齢黄斑変性症、網膜色素変性症等を挙げることができる。 The retinal disease to which the therapeutic agent of the present invention is targeted is not particularly limited as long as it is a retinal disease not caused by hyperglycemia. For example, the retina is damaged for some reason, the visual field is narrowed, or the visual acuity is impaired. Diseases that decrease can be mentioned. Specific examples thereof include age-related macular degeneration and retinitis pigmentosa, in which the macula, which is the central part of the retina, is damaged by aging.
　本発明の治療剤におけるＳＧＬＴ２阻害物質としては、フロリジン誘導体であり、ＳＧＬＴ２に結合しＳＧＬＴ２を介したナトリウム及び／又はグルコース取り込みに対して拮抗的な阻害作用を示すものであれば特に制限されるものではない。 The SGLT2 inhibitor in the therapeutic agent of the present invention is particularly limited as long as it is a phlorizin derivative that binds to SGLT2 and exhibits an antagonistic inhibitory effect on sodium and / or glucose uptake via SGLT2. is not.
　ＳＧＬＴ２阻害物質としては、カナグリフロジン、イプラグリフロジン、ダパグリフロジン、ルセオグリフロジン、エンパグリフロジン、トホグリフロジン、エルツグリフロジン等を例示することができ、具体的には、既存のＳＧＬＴ２阻害薬の有効成分である、カナグリフロジン水和物（Ｃ２４Ｈ２５ＦＯ５Ｓ・１／２Ｈ２Ｏ）、イプラグリフロジン Ｌ－プロリン（Ｃ２１Ｈ２１ＦＯ５Ｓ・Ｃ５Ｈ９ＮＯ２）、ダパグリフロジンプロピレングリコール水和物（Ｃ２１Ｈ２５ＣｌＯ６・Ｃ３Ｈ８Ｏ２・Ｈ２Ｏ）、ルセオグリフロジン水和物（Ｃ２３Ｈ３０Ｏ６Ｓ・ｘＨ２Ｏ）、エンパグリフロジン（Ｃ２３Ｈ２７ＣｌＯ７）、トホグリフロジン水和物（Ｃ２２Ｈ２６Ｏ６・Ｈ２Ｏ）や、エルツグリフロジンピドロ酸塩（Ｃ２２Ｈ２５ＣｌＯ７・Ｃ５Ｈ７ＮＯ３）等を例示することができる。 Examples of SGLT2 inhibitors include canagliflozin, ipragliflozin, dapagliflozin, luseogliflozin, empagliflozin, tofogliflozin, and ertugliflozin, and specifically, the active ingredient of an existing SGLT2 inhibitor. Canaglyflozin hydrate (C 24 H 25 FO 5 S · 1 / 2H 2 O), ipragliflozin L-proline (C 21 H 21 FO 5 S · C 5 H 9 NO 2 ), Dapa Glyflozin propylene glycol hydrate (C 21 H 25 ClO 6 · C 3 H 8 O 2 · H 2 O), Luceogliflozin hydrate (C 23 H 30 O 6 S · xH 2 O), empagliflozin (C 23 H 27 ClO 7 ), tofogliflozin hydrate (C 22 H 26 O 6 · H 2 O), eltzgliflozin pidroate (C 22 H 25 ClO 7 · C 5 H 7 NO 3 ), etc. Can be exemplified.
　なお、上記のように、本発明においては、例えば「カナグリフロジン」という用語は、下記のカナグリフロジン構造を備えたものを意味し、医薬上許容される水和物、アルコール付加物、アミノ酸付加物、塩等を含むものである。その他の「イプラグリフロジン」等のＳＧＬＴ２阻害物質も同様である。 As described above, in the present invention, for example, the term "canagliflozin" means a substance having the following canagliflozin structure, which is a pharmaceutically acceptable hydrate, alcohol adduct, or amino acid. It contains adducts, salts, etc. The same applies to other SGLT2 inhibitors such as "ipragliflozin".
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　本発明の治療剤の投与量としては、血糖降下が認められる投与量であってもよいし、それより少ない血糖降下作用が認められない低用量であってもよい。すなわち、本発明の治療剤は、ＳＧＬＴ２抑制の尿中有効濃度に達しない低用量の投与でも、血中または網膜組織において視細胞などの網膜構成細胞のＳＧＬＴ２を阻害する有効濃度に達して網膜機能保護的に作用するものである。 The dose of the therapeutic agent of the present invention may be a dose at which hypoglycemic action is observed, or a low dose at which a lower hypoglycemic effect is not observed. That is, the therapeutic agent of the present invention reaches an effective concentration that inhibits SGLT2 of retinal constituent cells such as photoreceptor cells in blood or retinal tissue even at a low dose that does not reach the effective concentration in urine that suppresses SGLT2, and retinal function. It acts protectively.
　本発明において血糖降下作用が認められない低用量としては、血糖が有意に降下しない量であり、例えば、ＳＧＬＴ２阻害物質が認可されている血糖降下薬の有効成分の場合には、認可された最小投与量よりも少ない用量を意味する。その下限は、効果が奏される範囲で適宜決定すればよいが、例えば、カナグリフロジン水和物は、認可された最小投与量の１／１００程度である。イプラグリフロジン Ｌ－プロリンは、最小投与量における最高血中濃度（Ｃｍａｘ）がカナグリフロジンと類似し、阻害活性を示すＩＣ５０値も類似することから、同様に、認可された最小投与量の１／１００程度である。ダパグリフロジンプロピレングリコール水和物、ルセオグリフロジン水和物、エンパグリフロジン、トホグリフロジン水和物の場合は、最小投与量における最高血中濃度（Ｃｍａｘ）がカナグリフロジンの約１／１０程度であり、ＩＣ５０値は類似することから、１／１０程度である。 In the present invention, the low dose at which the hypoglycemic effect is not observed is an amount that does not significantly lower blood glucose, and for example, in the case of the active ingredient of a hypoglycemic agent for which an SGLT2 inhibitor is approved, the approved minimum amount. Means a dose less than the dose. The lower limit may be appropriately determined within the range in which the effect is exhibited. For example, canagliflozin hydrate is about 1/100 of the approved minimum dose. Ipragliflozin L-proline has a maximum blood concentration (Cmax) similar to that of canagliflozin at the minimum dose, and an IC50 value showing inhibitory activity is also similar. It is about / 100. In the case of dapagliflozin propylene glycol hydrate, luseogliflozin hydrate, empagliflozin, tofogliflozin hydrate, the maximum blood concentration (Cmax) at the minimum dose is about 1/10 of canagliflozin. Since the IC50 values are similar, they are about 1/10.
　具体的には、血糖降下薬として認可されているカナグリフロジン水和物では、成人１日当たり（カナグリフロジンとして）１００ｍｇ未満であり、９０ｍｇ以下であってもよく、７０ｍｇ以下であってもよく、５０ｍｇ以下であってもよく、３０ｍｇ以下であってもよく、１０ｍｇ以下であってもよく、５ｍｇ以下であってもよく、その下限は、１ｍｇ程度である。 Specifically, the canagliflozin hydrate approved as a hypoglycemic agent is less than 100 mg (as canagliflozin) per adult per day, may be 90 mg or less, or may be 70 mg or less. , 50 mg or less, 30 mg or less, 10 mg or less, 5 mg or less, and the lower limit thereof is about 1 mg.
　イプラグリフロジン Ｌ－プロリンでは、成人１日当たり（イプラグリフロジンとして）５０ｍｇ未満であり、４０ｍｇ以下であってもよく、３０ｍｇ以下であってもよく、２０ｍｇ以下であってもよく、１０ｍｇ以下であってもよく、５ｍｇ以下であってもよく、１ｍｇ以下であってもよく、その下限は、０．５ｍｇ程度である。 Ipragliflozin L-proline is less than 50 mg per day (as ipragliflozin) for adults, may be 40 mg or less, 30 mg or less, 20 mg or less, or 10 mg or less. It may be 5 mg or less, or 1 mg or less, and the lower limit thereof is about 0.5 mg.
　ダパグリフロジンプロピレングリコール水和物では、成人１日当たり（ダパグリフロジンとして）５ｍｇ未満であり、４ｍｇ以下であってもよく、３ｍｇ以下であってもよく、２ｍｇ以下であってもよく、１ｍｇ以下であってもよく、その下限は、０．５ｍｇ程度である。 Dapagliflozin propylene glycol hydrate is less than 5 mg per day (as dapagliflozin) for adults, may be 4 mg or less, 3 mg or less, 2 mg or less, or 1 mg or less. It may be present, and the lower limit thereof is about 0.5 mg.
　ルセオグリフロジン水和物では、成人１日当たり（ルセオグリフロジンとして）２．５ｍｇ未満であり、２ｍｇ以下であってもよく、１．５ｍｇ以下であってもよく、１ｍｇ以下であってもよく、０．５ｍｇ以下であってもよく、その下限は、０．２５ｍｇ程度である。 Luceogliflozin hydrate is less than 2.5 mg (as luseogliflozin) per day for adults, may be 2 mg or less, 1.5 mg or less, or 1 mg or less. It may be 0.5 mg or less, and the lower limit thereof is about 0.25 mg.
　エンパグリフロジンでは、成人１日当たり１０ｍｇ未満であり、９ｍｇ以下であってもよく、６ｍｇ以下であってもよく、４ｍｇ以下であってもよく、２ｍｇ以下であってもよく、その下限は、０．１ｍｇ程度である。 Empagliflozin is less than 10 mg per day for adults, may be 9 mg or less, 6 mg or less, 4 mg or less, 2 mg or less, and the lower limit is 0. It is about 1 mg.
　トホグリフロジン水和物では、成人１日当たり（トホグリフロジンとして）２０ｍｇ未満であり、１８ｍｇ以下であってもよく、１５ｍｇ以下であってもよく、１０ｍｇ以下であってもよく、５ｍｇ以下であってもよく、その下限は、２ｍｇ程度である。 For tofogliflozin hydrate, the daily adult (as tofogliflozin) is less than 20 mg, may be 18 mg or less, 15 mg or less, 10 mg or less, 5 mg or less, and may be. The lower limit is about 2 mg.
　本発明の治療剤の投与形態としては、経口用、注射用等が挙げられるが、既存のＳＧＬＴ２阻害薬（血糖降下薬）同様、経口用であることが好ましい。また、本発明の治療剤の形態としては、錠状、顆粒状、粉末状、カプセル状、液状等、各種形態を挙げることができる。 Examples of the administration form of the therapeutic agent of the present invention include oral use, injection use, etc., but it is preferably oral use as in the existing SGLT2 inhibitor (hypoglycemic agent). In addition, examples of the form of the therapeutic agent of the present invention include various forms such as tablets, granules, powders, capsules, and liquids.
　また、本発明の治療剤を用いた高血糖に起因しない網膜疾患の治療方法としては、ＳＧＬＴ２阻害物質を有効成分とする本発明の治療剤を、血糖降下が認められる用量又は血糖降下が認められない用量で患者に投与する方法であれば特に制限されるものではなく、上記のように、その投与方法としては、経口投与、注射投与等を例示することができる。本発明の治療剤の詳細及びその投与量、並びに治療対象の網膜疾患の具体例等については上記のとおりである。 Further, as a method for treating a retinal disease not caused by hyperglycemia using the therapeutic agent of the present invention, the therapeutic agent of the present invention containing an SGLT2 inhibitor as an active ingredient is found to have a hypoglycemic dose or a hypoglycemic dose. The method is not particularly limited as long as it is administered to a patient at a non-dose dose, and as described above, oral administration, injection administration and the like can be exemplified as the administration method. Details of the therapeutic agent of the present invention, its dose, specific examples of the retinal disease to be treated, and the like are as described above.
［予備試験］
　ＢＡＬＢ／ｃマウスに、光照射（８０００ｌｕｘ、１０時間）を行い、その後１週間飼育した。既存のＳＧＬＴ２阻害薬イプラグリフロジンを０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日の量で、光照射日を含み４日間経口投与し、体重及び血糖に対する効果を確認した。なお、本モデルは、加齢黄斑変性症モデルとして汎用されている。 [Preliminary test]
BALB / c mice were irradiated with light (8000 lux, 10 hours) and then bred for 1 week. The existing SGLT2 inhibitor ipragliflozin was orally administered at 0.03 mg / kg / day and 0.1 mg / kg / day for 4 days including the day of light irradiation, and the effect on body weight and blood glucose was confirmed. This model is widely used as an age-related macular degeneration model.
　図１及び図２に、既存のＳＧＬＴ２阻害薬イプラグリフロジン０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日の投与の場合の体重および血糖値の結果を示す。
　図１及び図２に示すように、いずれの投与量においても、イプラグリフロジン非投与の場合と比較して体重、血糖に変化は認められなかった。なお、尿糖についても、体重、血糖と同様に、イプラグリフロジン非投与の場合と比較して変化は認められなかった。 1 and 2 show the results of body weight and blood glucose levels when the existing SGLT2 inhibitor ipragliflozin 0.03 mg / kg / day and 0.1 mg / kg / day were administered.
As shown in FIGS. 1 and 2, no change was observed in body weight and blood glucose at any dose as compared with the case where ipragliflozin was not administered. As with body weight and blood glucose, no change was observed in urinary sugar as compared with the case where ipragliflozin was not administered.
［実施例１］
　ヘマトキシリン・エオジン染色にて、イプラグリフロジンの血糖降下を認めない低用量（０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日）における網膜に対する保護効果を確認した。なお、イプラグリフロジンの投与期間は、予備試験同様、光照射日を含め４日間である。その結果を図３及び図４に示す。図４は、網膜の外顆粒層（視細胞を含む）の厚さを計測し、数値化したものである。 [Example 1]
Hematoxylin and eosin staining confirmed the protective effect of ipragliflozin on the retina at low doses (0.03 mg / kg / day and 0.1 mg / kg / day) without hypoglycemia. The administration period of ipragliflozin is 4 days including the day of light irradiation, as in the preliminary test. The results are shown in FIGS. 3 and 4. FIG. 4 shows the thickness of the outer nuclear layer (including photoreceptor cells) of the retina measured and quantified.
　図２に示すように、イプラグリフロジン０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日は、血糖降下を示さない投与量であるが、図３及び図４に示すように、このイプラグリフロジン０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日の投与で、ＡＭＤマウスの網膜で見られた膜の菲薄化の有意な改善が認められた。ヒトの加齢黄斑変性、特に萎縮型においては、網膜色素上皮が徐々に萎縮していき、網膜が障害され視力が徐々に低下していくことから、イプラグリフロジンによる網膜の保護効果により、最終的には視覚機能の改善が期待される。 As shown in FIG. 2, ipragliflozin 0.03 mg / kg / day and 0.1 mg / kg / day are doses that do not show hypoglycemia, but as shown in FIGS. 3 and 4, they are not shown. Administration of ipragliflozin 0.03 mg / kg / day and 0.1 mg / kg / day showed a significant improvement in membrane thinning seen in the retina of AMD mice. In human age-related macular degeneration, especially in the atrophic type, the retinal pigment epithelium gradually atrophies, the retina is damaged and the visual acuity gradually deteriorates. It is expected that the visual function will be improved.
［実施例２］
　ヘマトキシリン・エオジン染色にて、ルセオグリフロジンの血糖降下を認めない低用量（０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日）における網膜に対する保護効果を確認した。なお、ルセオグリフロジンの投与期間は、光照射日を含め４日間である。その結果を図５及び図６に示す。図６は、網膜の外顆粒層（視細胞を含む）の厚さを計測し、数値化したものである。 [Example 2]
Hematoxylin and eosin staining confirmed the protective effect of luseogliflozin on the retina at low doses (0.03 mg / kg / day and 0.1 mg / kg / day) without hypoglycemia. The administration period of luseogliflozin is 4 days including the day of light irradiation. The results are shown in FIGS. 5 and 6. FIG. 6 shows the thickness of the outer nuclear layer (including photoreceptor cells) of the retina measured and quantified.
　図５及び図６に示すように、このルセオグリフロジン０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日の投与で、ＡＭＤマウスの網膜で見られた膜の菲薄化の有意な改善が認められた。 As shown in FIGS. 5 and 6, administration of this luseogliflozin 0.03 mg / kg / day and 0.1 mg / kg / day significantly improved the thinning of the membrane observed in the retina of AMD mice. Was recognized.
［実施例３］
　ヘマトキシリン・エオジン染色にて、トホグリフロジンの血糖降下を認めない低用量（０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日）における網膜に対する保護効果を確認した。なお、トホグリフロジンの投与期間は、光照射日を含め４日間である。その結果を図７に示す。図７は、網膜の外顆粒層（視細胞を含む）の厚さを計測し、数値化したものである。 [Example 3]
Hematoxylin and eosin staining confirmed the protective effect of tofogliflozin on the retina at low doses (0.03 mg / kg / day and 0.1 mg / kg / day) without hypoglycemia. The administration period of tofogliflozin is 4 days including the day of light irradiation. The result is shown in FIG. FIG. 7 shows the thickness of the outer nuclear layer (including photoreceptor cells) of the retina measured and quantified.
　図７に示すように、このトホグリフロジン０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日の投与で、ＡＭＤマウスの網膜で見られた膜の菲薄化の有意な改善が認められた。 As shown in FIG. 7, administration of 0.03 mg / kg / day and 0.1 mg / kg / day of tofogliflozin significantly improved the thinning of the membrane observed in the retina of AMD mice.
［実施例４］
　ヘマトキシリン・エオジン染色にて、カナグリフロジンの血糖降下を認めない低用量（０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日）における網膜に対する保護効果を確認した。なお、カナグリフロジンの投与期間は、光照射日を含め４日間である。その結果を図８に示す。図８は、網膜の外顆粒層（視細胞を含む）の厚さを計測し、数値化したものである。 [Example 4]
Hematoxylin and eosin staining confirmed the protective effect of canagliflozin on the retina at low doses (0.03 mg / kg / day and 0.1 mg / kg / day) without hypoglycemia. The administration period of canagliflozin is 4 days including the day of light irradiation. The result is shown in FIG. FIG. 8 shows the thickness of the outer nuclear layer (including photoreceptor cells) of the retina measured and quantified.
　図８に示すように、このカナグリフロジン０．０３ｍｇ／ｋｇ／日、及び０．１ｍｇ／ｋｇ／日の投与で、ＡＭＤマウスの網膜で見られた膜の菲薄化の有意な改善が認められた。 As shown in FIG. 8, administration of 0.03 mg / kg / day and 0.1 mg / kg / day of canagliflozin significantly improved the thinning of the membrane observed in the retina of AMD mice. It was.
　以上のように、本発明の治療剤は、血糖降下を認めない用量において、加齢黄斑変性症を改善する効果をもつことが明らかとなった。 As described above, it has been clarified that the therapeutic agent of the present invention has an effect of improving age-related macular degeneration at a dose that does not cause hypoglycemia.
　本発明の治療剤は、加齢黄斑変性症等の治療薬としての新たな適応拡大を可能とするものであり、産業上の有用性は高い。

  The therapeutic agent of the present invention enables new indications to be expanded as a therapeutic agent for age-related macular degeneration and the like, and is highly industrially useful.

Claims (4)

  1. 　フロリジン誘導体であるナトリウム／グルコース共輸送体２阻害物質（ＳＧＬＴ２阻害物質）を有効成分とすることを特徴とする高血糖に起因しない網膜疾患の治療剤。 A therapeutic agent for retinal diseases not caused by hyperglycemia, which comprises a sodium / glucose cotransporter 2 inhibitor (SGLT2 inhibitor) which is a phlorizin derivative as an active ingredient.
  2. 　血糖降下が認められない低用量で投与されるよう用いられることを特徴とする請求項１記載の治療剤。 The therapeutic agent according to claim 1, characterized in that it is used so as to be administered at a low dose in which no hypoglycemia is observed.
  3. 　ＳＧＬＴ２阻害物質が、カナグリフロジン、イプラグリフロジン、ダパグリフロジン、ルセオグリフロジン、エンパグリフロジン、トホグリフロジン及びエルツグリフロジンから選ばれる少なくとも１種であることを特徴とする請求項１又は２記載の治療剤。 The therapeutic agent according to claim 1 or 2, wherein the SGLT2 inhibitor is at least one selected from canagliflozin, ipragliflozin, dapagliflozin, luseogliflozin, empagliflozin, tofogliflozin and ertugliflozin. ..
  4. 　高血糖に起因しない網膜疾患が、加齢黄斑変性症であることを特徴とする請求項１～３のいずれか記載の治療剤。

          The therapeutic agent according to any one of claims 1 to 3, wherein the retinal disease not caused by hyperglycemia is age-related macular degeneration.
PCT/JP2019/019009 2019-05-14 2019-05-14 Therapeutic agent for retinal diseases WO2020230251A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP2019/019009 WO2020230251A1 (en) 2019-05-14 2019-05-14 Therapeutic agent for retinal diseases

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2019/019009 WO2020230251A1 (en) 2019-05-14 2019-05-14 Therapeutic agent for retinal diseases

Publications (1)

Publication Number Publication Date
WO2020230251A1 true WO2020230251A1 (en) 2020-11-19

Family

ID=73289878

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/019009 WO2020230251A1 (en) 2019-05-14 2019-05-14 Therapeutic agent for retinal diseases

Country Status (1)

Country Link
WO (1) WO2020230251A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018030822A (en) * 2016-08-26 2018-03-01 登與志 井口 Retinopathy therapeutic agent
WO2018043463A1 (en) * 2016-08-30 2018-03-08 国立大学法人新潟大学 Drug for removing aged cells

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018030822A (en) * 2016-08-26 2018-03-01 登與志 井口 Retinopathy therapeutic agent
WO2018043463A1 (en) * 2016-08-30 2018-03-08 国立大学法人新潟大学 Drug for removing aged cells

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAGAI, R. ET AL.: "Significance of Advanced Glycation End Products in Aging-Related Disease", ANTI-AGING MEDICINE, vol. 7, no. 10, 16 September 2010 (2010-09-16), pages 112 - 119, XP055759995 *

Similar Documents

Publication Publication Date Title
Allansmith et al. Ocular allergy and mast cell stabilizers
RU2686670C2 (en) Treatment of allergic rhinitis using combination of mometasone and olopatadine
CN107847520A (en) Treat the method and composition of inflammatory conditions and immunological diseases
CA2724133A1 (en) Medicine consisting of concomitant use or combination of dpp-iv inhibitor and other diabetic medicine
EP2380569B1 (en) Osmolyte for reduction of side effects of steroids or antihistaminica
US10821126B2 (en) Agent for treating retinopathy
JP6831961B2 (en) Retinal disease therapeutic agent
WO2020230251A1 (en) Therapeutic agent for retinal diseases
WO2019092770A1 (en) Therapeutic agent for retinal disease
JP2004091473A (en) Therapeutic agent for improving chromatosis
WO2010117077A1 (en) Therapeutic agent for chorioretinal diseases comprising sirolimus derivative as active ingredient
WO2011091461A1 (en) Compounds for use in the treatment of diseases
JP2019112472A (en) Retinopathy therapeutic agent
ES2356244T3 (en) PREPARATION OF FLUPIRTINE FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES OF THE VISUAL SYSTEM AND DIATEBES MELLITUS.
JP6563375B2 (en) Nephropathy treatment
US20140275124A1 (en) Methods for treating eye disorders using dipyridamole
Barishak et al. Histology of the iris in geese and ducks photosensitized by ingestion of Ammi majus seeds
KR102275250B1 (en) Composition for preventing and treating dry eye syndrome comprising selenium and propolis as active ingredients
WO2019087239A1 (en) Therapeutic agent for nephropathy
US7906157B2 (en) Use of extracts of Capraria biflora in the prevention and/or treatment of senile cataracts
RU2326668C2 (en) Method of recurrent pterygium medical treatment
KR20220166203A (en) Pharmaceutical composition for the prevention or treatment of degenerative eye diseases
JP2023539391A (en) Use of sesquiterpene lactone compounds in the manufacture of optic neuritis treatment drugs
JP2023043810A (en) Allergic conjunctivitis therapeutic agent
JP2023043699A (en) Allergic conjunctivitis therapeutic agent

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19928479

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19928479

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP