JP6831961B2 - Retinal disease therapeutic agent - Google Patents

Description

The present invention relates to therapeutic agents for treating retinal diseases.

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.

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.

On the other hand, an SGLT2 inhibitor inhibits sodium / glucose co-transporter 2 (sodium / glucose co-transporter2: SGLT2), which is specifically present in the proximal tubule of the kidney and is reabsorbing glucose, and urine. It is an antidiabetic drug that exhibits a hypoglycemic effect by promoting glucose excretion from Glucose, and has already been clinically applied to 6 types of SGLT2 inhibitors (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.

Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacil Sci 2011; 32: 63-71 Zaccadi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diab Obes Metab 2016; 18: 783-94

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.

In studying the action and effect of an SGLT2 inhibitor as an antidiabetic drug 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 tubule, glucose-induced retinopathy (retinopathy caused by glucose) in low-dose administration in which existing SGLT2 inhibitors show a hypoglycemic effect and do not show a hypoglycemic effect ( It was found that it exerts an improving effect on (retinopathy caused by hyperglycemia) (PCT / JP2016 / 86658).

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.

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) 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 no hypoglycemia is observed.
[3] The above-mentioned [1] or [2], wherein the SGLT2 inhibitor is at least one selected from canagliflozin, ipragliflozin, dapagliflozin, luseogliflozin, empagliflozin and tofogliflozin. Therapeutic agent.
[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.

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, which 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.

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. 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. It is a figure which shows the hematoxylin-eosin staining of the retina of the age-related macular degeneration model mouse. "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. 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. "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.

The therapeutic agent of the present invention is a therapeutic agent for retinal diseases not caused by hyperglycemia, and contains an SGLT2 inhibitor 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. 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 retinal constituent cells.

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 retinal constituent cells is suppressed and the retinal function is improved. In fact, the SGLT2 inhibitor showed an improving 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. 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.

The SGLT2 inhibitor in the therapeutic agent of the present invention is not particularly limited as long as it binds to SGLT2 and exhibits an antagonistic inhibitory effect on sodium and / or glucose uptake via SGLT2.

Examples of the SGLT2 inhibitor include canagliflozin, ipragliflozin, dapagliflozin, luseogliflozin, empagliflozin, tohogliflozin, and the like. Specifically, canagliflozin, which is an active ingredient of existing SGLT2 inhibitors. Glyflozin 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 ), dapagliflozin 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 ), tohogliflozin hydrate (C ₂₂ H ₂₆ O ₆ · H ₂ O) and the like can be exemplified.

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 includes additives and the like. 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.

In the present invention, the low dose at which no hypoglycemic effect is observed is an amount that does not significantly lower blood glucose, and in the case of the active ingredient of a hypoglycemic agent for which an SGLT2 inhibitor is approved, the approved minimum dose. Means less 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. Since ipragliflozin L-proline has a similar maximum blood concentration (Cmax) at the minimum dose and a similar IC50 value showing inhibitory activity, it is also 1 of the approved minimum dose. 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.

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.

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.

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.

Examples of the administration form of the therapeutic agent of the present invention include oral use, injection use, and the like, 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.

In addition, as a method for treating retinal diseases 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.

[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.

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 hypoglycemic activity. 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.

As shown in FIG. 2, ipragliflozin 0.03 mg / kg / day and 0.1 mg / kg / day are doses showing no hypoglycemic effect, 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 visual acuity gradually deteriorates. Therefore, the protective effect of the retina by ipragliflozin is the final factor. It is expected that the visual function will be improved.

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 in which hypoglycemia is not observed.

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

Claims (2)

It is characterized by containing at least one sodium / glucose cotransporter 2 inhibitor (SGLT2 inhibitor) selected from canagliflozin, ipragliflozin, dapagliflozin, luseogliflozin, empagliflozin and tofogliflozin as an active ingredient. A therapeutic agent for age-related yellow spot degeneration. The therapeutic agent according to claim 1, wherein the therapeutic agent is used so as to be administered at a low dose in which no hypoglycemia is observed.