WO2020230251A1 - Agent thérapeutique contre des maladies de la rétine - Google Patents

Agent thérapeutique contre des maladies de la rétine Download PDF

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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
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therapeutic agent
day
age
amd
ipragliflozin
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PCT/JP2019/019009
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English (en)
Japanese (ja)
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登與志 井口
真由実 大和
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株式会社カルナヘルスサポート
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Priority to PCT/JP2019/019009 priority Critical patent/WO2020230251A1/fr
Publication of WO2020230251A1 publication Critical patent/WO2020230251A1/fr

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    • 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.

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Abstract

L'invention concerne un agent thérapeutique contre des maladies de la rétine, telles que la dégénérescence maculaire liée à l'âge, qui contient comme principe actif une substance inhibitrice du transporteur 2 sodium-glucose (SGLT2), ladite substance étant un dérivé de la phloridzine, tel que la canagliflozine, l'ipragliflozine, la dapagliflozine, la luséogliflozine, l'empagliflozine, la tofogliflozine et l'ertugliflozine.
PCT/JP2019/019009 2019-05-14 2019-05-14 Agent thérapeutique contre des maladies de la rétine WO2020230251A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018030822A (ja) * 2016-08-26 2018-03-01 登與志 井口 網膜症治療剤
WO2018043463A1 (fr) * 2016-08-30 2018-03-08 国立大学法人新潟大学 Médicament pour éliminer des cellules vieillissantes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018030822A (ja) * 2016-08-26 2018-03-01 登與志 井口 網膜症治療剤
WO2018043463A1 (fr) * 2016-08-30 2018-03-08 国立大学法人新潟大学 Médicament pour éliminer des cellules vieillissantes

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 *

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