WO2019087239A1 - Therapeutic agent for nephropathy - Google Patents

Abstract

[Problem] To provide a therapeutic agent for treating and/or ameliorating nephropathy that is not associated with hyperglycemia. [Solution] A therapeutic agent for nephropathy that is not associated with hyperglycemia, which is characterized by containing, as an active ingredient, a sodium/glucose cotransporter 2 (SGLT2) inhibitor and is intended to be administered at such a dose that the dropping in blood glucose level cannot be observed.

Description

Nephropathy treatment

The present invention relates to a therapeutic agent for treating nephropathy.

Due to the high blood pressure and the severeness of diabetes etc., the function of the kidney decreases as chronic renal failure. If the renal function declines, artificial dialysis treatment will be required, which will not only cause problems in daily life, but will also be a major medical economic problem. However, there is currently no specific drug to cure renal failure, and it is important to delay the progression of chronic renal failure.

On the other hand, SGLT2 inhibitors are antidiabetic agents that exhibit hypoglycemic action by inhibiting sodium / glucose co-transporter 2 (SGLT2) and promoting urinary glucose excretion, Clinical applications of six SGLT2 inhibitors have already been conducted (see, for example, Non-Patent Documents 1 and 2). At present, this SGLT2 inhibitor is approved only as a hypoglycemic drug for treating diabetes.

By the way, this SGLT2 inhibitor has recently been reported to have the possibility of having a nephropathy improving effect at a normal dose, and has been attracting attention, but for use as a therapeutic agent for nephropathy, the mechanism of the hypoglycemic action of this drug As side effects based on increased urinary glucose excretion, there are problems such as hypoglycemia, polyuria and pollakiuria, dehydration, urinary tract infections and genital infections, and an increase in ketone bodies. In addition, with regard to the nephritic improvement effect by SGLT2 inhibitor, the mechanism through the SGLT2 inhibitory effect of the proximal tubule which is the mechanism of the glycemic effect action (promotion of urinary excretion of sodium through SGLT2 inhibition of the proximal tubule) Effects are estimated, and in patients with moderate or higher renal function such as renal failure, the excretion of SGLT2 inhibitors into urine is reduced, so it is thought that no hypoglycemic effect can be obtained, and its use is Not recommended

Bailey C. 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 nephropathy.

While the present inventors are studying the effect of SGLT2 inhibitor as a hypoglycemic drug for diabetes, first of all, the SGLT2 inhibitor acts on the actual dose of the SGLT2 inhibitor. Focusing on the fact that only a small amount has reached the tubule, glucose-induced nephropathy (nephropathy caused by hyperglycemia) at low doses such that existing SGLT2 inhibitors show no hypoglycemic action Was found to exert an improvement effect on (PCT / JP2016 / 86657).

As a result of further studies, the present inventors have found that a low dose of SGLT2 inhibitor has a protective effect even in renal failure model mice not showing hyperglycemia. That is, even in completely different diseases not caused by excessive influx of glucose into renal constituent cells due to hyperglycemia (diseases not caused by hyperglycemia), nephropathy is a mechanism such as suppression of sodium and / or glucose uptake It has been found that the present invention exerts the improvement effect of the present invention.

That is, the present invention is as follows.
[1] A sodium / glucose cotransporter 2 inhibitor (SGLT2 inhibitor) is used as an active ingredient, and it is used to be administered at a low dose at which no hypoglycemia is observed. Therapeutic agent.
[2] The therapeutic agent according to the above-mentioned [1], wherein the SGLT2 inhibitor is at least one selected from canagliflozin, ipragliflozin, dapagliflozin, ruseoglyflozin, empagliflozin and tofogliflozin.
[3] The therapeutic agent of the above-mentioned [1] or [2], wherein the nephropathy not caused by hyperglycemia is a disease of the kidney based on hyperuricemia.
[4] The therapeutic agent according to any one of the above [1] to [3], wherein the nephropathy not caused by hyperglycemia is a disease of the kidney accompanied by an inflammatory reaction of kidney tissue.
[5] The therapeutic agent according to any one of the above [1] to [4], wherein the nephropathy not caused by hyperglycemia is a disease of the kidney accompanied by fibrosis of renal tissue stroma.

According to the therapeutic agent of the present invention, it is possible to treat nephropathy not caused by hyperglycemia by administration of a low dose having no hypoglycemic action which has not been clinically applied at present. Since the therapeutic agent of the present invention is effective when administered at low doses, hypoglycemia, polyuria, pollakiuria, dehydration, and urinary tract, which are the main side effects due to the urinary glucose excretion promoting action of existing SGLT2 inhibitors. There is no problem such as infection / genital infection, increase of ketone body, and the safety is also extremely high. In addition, since the therapeutic agent of the present invention is not affected by decreased urine output, it is also effective for patients with impaired renal function such as renal failure. At present, considering that there is no chronic renal failure therapeutic agent, the therapeutic agent of the present invention enables a new indication expansion as a nephropathy therapeutic agent.

It is a figure which shows the effect of ipragliflozin administration on the weight of a renal failure model mouse. "ND" represents control normal diet fed mice (n = 8), "AD" represents 0.25% adenine containing diet fed mice. “0” represents ipragliflozin non-administered AD mouse (n = 8), “0.03” represents ipragliflozin 0.03 mg / kg / day administered AD mouse (n = 7), “0.1” represents an ipragliflozin 0.1 mg / kg / day-administered AD mouse (n = 8). “***” represents P <0.005 vs ND mice, and “ns” represents no significant difference from ipragliflozin non-administered AD mice. It is a figure which shows the effect of ipragliflozin administration on blood glucose of a renal failure model mouse. "ND" represents control normal diet fed mice (n = 8), "AD" represents 0.25% adenine containing diet fed mice. “0” represents ipragliflozin non-administered AD mouse (n = 8), and “0.03” represents ipragliflozin 0.03 mg / kg / day administered db / db mouse (n = 7) “0.1” represents an ipragliflozin 0.1 mg / kg / day-administered AD mouse (n = 8). “***” represents P <0.005 vs ND mice, and “ns” represents no significant difference from ipragliflozin non-administered AD mice. FIG. 6 shows the effect of ipragliflozin administration on renal hypertrophy (renal weight corrected for body weight) in renal failure model mice. "ND" represents control normal diet fed mice (n = 8), "AD" represents 0.25% adenine containing diet fed mice. “0” represents ipragliflozin non-administered AD mouse (n = 8), “0.03” represents ipragliflozin 0.03 mg / kg / day administered AD mouse (n = 7), “0.1” represents an ipragliflozin 0.1 mg / kg / day-administered AD mouse (n = 8). “***” represents P <0.005 vs ND mice, “#” represents P <0.05 vs ipragliflozin non-administered AD mice. FIG. 6 shows the effect of ipragliflozin administration on hematocrit levels in renal failure model mice. "ND" represents control normal diet fed mice (n = 8), "AD" represents 0.25% adenine containing diet fed mice. “0” represents ipragliflozin non-administered AD mouse (n = 8), “0.03” represents ipragliflozin 0.03 mg / kg / day administered AD mouse (n = 7), “0.1” represents an ipragliflozin 0.1 mg / kg / day-administered AD mouse (n = 8). “***” represents P <0.005 vs ND mice, “#” represents P <0.05 vs ipragliflozin non-administered AD mice. FIG. 6 shows the effect of ipragliflozin administration on creatinine levels in renal failure model mice. "ND" represents control normal diet fed mice (n = 8), "AD" represents 0.25% adenine containing diet fed mice. “0” represents ipragliflozin non-administered AD mouse (n = 8), “0.03” represents ipragliflozin 0.03 mg / kg / day administered AD mouse (n = 7), “0.1” represents an ipragliflozin 0.1 mg / kg / day-administered AD mouse (n = 8). "*" And "***" represent P <0.05 vs ND mice, P <0.005 vs ND mice, and "#" and "###" represent P <0.05 I plug liflrosin Non-administered AD mice P <0.005 ipragliflozin non-administered AD mice. It is a figure which shows the correlation of the blood creatinine level and urine creatinine excretion in a renal failure model mouse. "White circle" represents a control normal food-fed mouse (n = 8), and "black circle" represents a 0.25% adenine-containing food-fed mouse. "Gray triangle" represents ipragliflozin 0.03 mg / kg / day administered AD mouse (n = 7), "grey circle" represents ipragliflozin 0.1 mg / kg / day administered AD mouse (n Represents 8). It is a figure which shows PAS (Periodic acid-Schiff) dyeing | staining of the kidney tissue of a renal failure model mouse. "ND" represents the kidney histology of control normal diet mice. "AD-1" is a kidney histology of 0.25% adenine-containing food-fed mice, and "AD-2" is an image of the accumulation site of urate in the kidney tissue of adenine-containing food-fed mice Represents “Ipra. (0.1) -1” is a renal histomorphogram of an AD mouse administered with ipragliflozin 0.1 mg / kg / day, “Ipra. It represents an image of a site where urate accumulates in the kidney tissue of a 1 mg / kg / day-administered AD mouse. The magnification is 200 times. It is a figure which shows the Masson trichrome staining of the kidney tissue of a renal failure model mouse. "ND" represents the kidney histology of control normal diet consuming mice, "AD" represents the kidney histology of 0.25% adenine containing diet consuming mice. “Ipra. (0.1)” represents a renal histology of AD mice administered ipragliflozin 0.1 mg / kg / day. The magnification is 100 times.

The therapeutic agent of the present invention is a therapeutic agent for nephropathy not caused by hyperglycemia, and is characterized in that it comprises an SGLT2 inhibitor as an active ingredient and is administered at a low dose at which hypoglycemia is not observed. Examples of the therapeutic agent of the present invention include a mode in which a low dose of an active ingredient in which hypoglycemia is not observed is contained in a single dose preparation.

In the present invention, it was found that the SGLT2 inhibitor has a renoprotective effect by a mechanism completely different from tubular SGLT2 suppression at low dose administration which does not recognize the hypoglycemic action currently applied clinically. is there. That is, in the present invention, it has been found that the SGLT2 inhibitor exhibits renal function protective action by suppressing the uptake of sodium and / or glucose into renal constituent cells at low dose administration.

According to the therapeutic agent of the present invention, even in nephropathy not exhibiting hyperglycemia, it is considered that the uptake of sodium and / or glucose into renal constituent cells is suppressed to improve the renal function. In fact, the SGLT2 inhibitor showed improvement in renal hypertrophy and hematocrit levels of hyperuricemia-based renal failure mice and also showed improvement in creatinine levels. Furthermore, it showed the effect of improving inflammatory cell infiltration and interstitial fibrosis.

The nephropathy targeted by the therapeutic agent of the present invention is not particularly limited as long as it is nephropathy not caused by hyperglycemia, and, for example, chronic kidney disease (CKD), acute kidney injury (Acute) (kidney injury; AKI) etc. can be mentioned. Specifically, diseases of the kidney based on hyperuricemia, nephrosclerosis, nephritis, polycystic kidney, drug-induced nephropathy and the like can be mentioned. Since the therapeutic agent of the present invention is not affected by decreased urine output, it is also effective for patients with impaired renal function such as renal failure (for example, patients in the fourth stage (renal insufficiency).

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

Examples of SGLT2 inhibitors include canagliflozin, ipragliflozin, dapagliflozin, ruseoglyflozin, empagliflozin, tofogliflozin etc. Specifically, kanagar, which is an active ingredient of existing SGLT2 inhibitors, can be exemplified. Glyphrosin hydrate (C ₂₄ H ₂₅ FO ₅ S 1⁄2 H 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), Luseoglyph rosin hydrate (C ₂₃ H ₃₀ O ₆ S x H ₂ O), empagliflozin (C ₂₃ H) ₂₇ ClO ₇ ), tofogliflozin hydrate (C ₂₂ H ₂₆ O ₆ .H ₂ O), etc. can be exemplified.

As mentioned above, in the present invention, for example, the term "canagliflozin" means one having the following canagliflozin structure, and is a pharmaceutically acceptable hydrate, alcohol adduct, amino acid It includes additives and the like. The same applies to other SGLT2 inhibitors such as "ipragliflozin".

The therapeutic agent of the present invention ameliorates nephropathy by a mechanism completely different from the mechanism of promoting urinary glucose excretion by SGLT2 suppression of the proximal tubule, and the dose thereof is as described above, It exerts a nephropathy improving effect at a dose that does not show hypoglycemia. That is, the therapeutic agent of the present invention achieves an effective concentration which inhibits SGLT2 of renal constituent cells such as renal mesangial cells in blood or renal tissue even when low dose administration does not reach the urinary effective concentration of SGLT2 suppression. It acts protectively.

In the present invention, a low dose that does not show hypoglycemic action is an amount that does not significantly reduce blood glucose, for example, in the case of the active ingredient of a hypoglycemic drug for which an SGLT2 inhibitor has been approved, the approved minimum dose Means a dose less than the amount. The lower limit may be determined as appropriate as long as the effect is exhibited. For example, canagliflozin hydrate is about 1/100 of the approved minimum dose. Ipragliflozin L-Proline is similar to canagliflozin at the lowest dose with the highest blood concentration (Cmax), and similar IC50 values showing inhibitory activity as well. It is about / 100. In the case of dapagliflozin propylene glycol hydrate, luceoflyph rosin hydrate, empagliflozin hydrate, tofogliflozin hydrate, the maximum blood concentration (Cmax) at the minimum dose is about 1/10 that of canagliflozin Since the IC50 values are similar, it is about 1/10.

Specifically, canagliflozin hydrate approved as a hypoglycemic agent is less than 100 mg per day (as canagliflozin), may be 90 mg or less, and may be 70 mg or less. 50 mg or less, 30 mg or less, 10 mg or less, or 5 mg or less, and the lower limit thereof is about 1 mg.

Ipragliflozin L-Proline is less than 50 mg per day for an adult (as Ipragliflozin), may be 40 mg or less, may be 30 mg or less, may be 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 is about 0.5 mg.

Dapagliflozin propylene glycol hydrate is less than 5 mg per day (as dapagliflozin), may be 4 mg or less, may be 3 mg or less, may be 2 mg or less, and 1 mg or less. The lower limit may be about 0.5 mg.

In the case of ruseogliflozin hydrate, it is less than 2.5 mg per day of an adult (as ruseogliflozin), and may be 2 mg or less, 1.5 mg or less, or 1 mg or less. 0.5 mg or less may be sufficient, The minimum is about 0.25 mg.

In the case of empagliflozin, it may be less than 10 mg, may be 9 mg or less, 6 mg or less, 4 mg or less, or 2 mg or less per adult, and the lower limit may be 0 It is about .1 mg.

In the case of Tofogliflozin Hydrate, it is less than 20 mg per day (as Tophogliflozin), may be 18 mg or less, 15 mg or less, 10 mg or less, or 5 mg or less per adult (as Tohogliflozin). The lower limit is about 2 mg.

Examples of the administration form of the therapeutic agent of the present invention include for oral use, for injection and the like, but for the same as existing SGLT2 inhibitors (hypoglycemic agents), it is preferable for oral use. In addition, as forms of the therapeutic agent of the present invention, various forms such as tablets, granules, powders, capsules, liquids and the like can be mentioned.

In addition, as a method of treating nephropathy not caused by hyperglycemia using the therapeutic agent of the present invention, the therapeutic agent of the present invention containing the SGLT2 inhibitor as an active ingredient is administered to a patient at a dose at which hypoglycemia is not observed. The method is not particularly limited as long as it is a method, and as described above, oral administration, injection administration and the like can be exemplified as its administration method. Details of the therapeutic agent of the present invention and the dose thereof, and specific examples of the nephropathy to be treated, etc. are as described above.

[Preliminary test]
Starting at week 8 after birth of C57 / B16 mice, intake of a feed containing 0.25% of adenine was started, and the existing SGLT2 inhibitor ipragliflozin was 0.03 mg / kg / day, and 0.1 mg / kg / day. The daily dose was orally administered for 4 weeks to confirm the effect on body weight, blood sugar and urine sugar. In addition, by taking adenine, mice become hyperuricemia and cause renal damage, and the renal damage progresses to chronic renal failure.

FIGS. 1 and 2 show the results of body weight and blood glucose level in the case of administration of the existing SGLT2 inhibitor ipragliflozin 0.03 mg / kg / day and 0.1 mg / kg / day.
As shown in FIGS. 1 and 2, in the adenine intake group, a decrease in body weight and blood glucose was observed as compared to the normal food intake group, but at any dose of ipragliflozin, ipragliflozin was not administered. There was no change in body weight or blood glucose compared to the case of. As for body weight and blood sugar, no change was observed in urinary sugar as compared with the case of administration of ipragliflozin.

Example 1
The improvement effect on renal hypertrophy and hematocrit value of AD mice (Adenine-containing diet-ingested mice) at low doses (0.03, 0.1 mg / kg / day) not showing hypoglycemia of ipragliflozin was confirmed. The results are shown in FIG. 3 and FIG. FIG. 3 shows the results of evaluation at a ratio of kidney weight corrected by body weight, and FIG. 4 shows the results of evaluation of hematocrit value.

As shown in FIG. 2, ipragliflozin 0.03, 0.1 mg / kg / day is a dose that does not show hypoglycemia, but as shown in FIG. 3, this ipragliflozin 0.1 mg / kg At daily doses, there was a significant improvement in the proportion of increased kidney weight in AD mice. The hematocrit, which is an index of anemia, was also significantly improved by administration of 0.1 mg / kg / day of ipragliflozin. In addition, when it is in the state of renal function decline such as chronic renal failure, renal anemia is caused by the shortage of erythropoietin. Hematocrit is an indicator of this anemic condition, but its recovery means improvement of nephropathy.

Example 2
The improvement effect on creatinine levels of AD mice at low doses (0.03, 0.1 mg / kg / day) in which hypoglycemia of ipragliflozin was not observed was confirmed. The results are shown in FIG. 5 and FIG.

While decreased renal function raises creatinine levels in blood, as shown in FIG. 5, ipragliflozin (0.03, 0.1 mg / kg) improved creatinine levels in blood in a concentration-dependent manner . Also, as shown in FIG. 6, since the creatinine level in the blood was inversely correlated with the amount excreted in urine, ipragrifin rosin improved the function of the kidney, and creatinine, which is a waste product, was excreted normally. it is conceivable that.

[Example 3]
The improvement effect on pathological change of AD mouse kidney tissue at low dose (0.03, 0.1 mg / kg / day) not showing hypoglycemia of ipragliflozin was confirmed. The results are shown in FIG. 7 and FIG.

From the results of PAS staining for kidney tissue shown in FIG. 7, it was found that Ipragliflozin was not effective against tubular enlargement and prominent cell infiltration into the stroma, particularly infiltration of inflammatory cells into the vicinity of needle crystals of sodium urate. An improvement was observed at a dose of 1 mg / kg / day. Furthermore, from the results of Masson's trichrome staining shown in FIG. 8, the improvement effect was also confirmed for interstitial fiberization (portion stained blue).

As described above, it has been revealed that the therapeutic agent of the present invention has the effect of improving nephropathy not caused by hyperglycemia at low dose administration without hypoglycemia.

The therapeutic agent of the present invention enables new indications as a therapeutic agent for renal failure and the like, and is highly useful in industry.

Claims (2)

A therapeutic agent for nephropathy not caused by hyperglycemia, which comprises sodium / glucose cotransporter 2 inhibitor (SGLT2 inhibitor) as an active ingredient and is used to be administered at a low dose at which hypoglycemia is not observed. The therapeutic agent according to claim 1, wherein the SGLT2 inhibitor is at least one selected from canagliflozin, ipragliflozin, dapagliflozin, luseoglyflozin, empagliflozin and tofogliflozin.

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