WO2022059694A1 - Composition for improving renal function - Google Patents

Abstract

The present invention provides a new use of 1,5-anhydrofructose and 1,5-anhydroglucitol that is a metabolic product of 1,5-anhydrofructose. The present invention pertains to a composition for improving renal function, said composition comprising 1,5-anhydrofructose and/or 1,5-anhydroglucitol as an active ingredient.

Description

Composition for improving renal function

The present invention relates to a composition for improving renal function.

The kidney excretes waste products in the body, maintains the water balance in the body, maintains the homeostasis of electrolytes in the body, and maintains the acid-base balance in the body through this. It has various functions such as the production and secretion of vitamin D and the expression and regulation of vitamin D that regulates calcium and phosphorus metabolism, and is an important organ essential for life support.

The body has two kidneys on the left and right, each of which has about 1 million minimum functional units, the nephron (each consisting of one glomerular and tubular pair) performing the above functions. , The reserve is great. However, nephrons do not have the ability to regenerate, and as a result, renal function gradually declines with aging (age-related decline in renal function). This decrease in renal function is caused by renal dysfunction (Chronic Kidney Disease, CKD) due to metabolic syndrome (hypertension, diabetes, hyperlipidemia, etc.), hyperuricemia, and the use of drugs (anticancer drug use, etc.). Accelerated by the complications, the result is renal failure, eventually leading to a condition called uricemia, which makes life-sustaining difficult. In recent years, artificial dialysis has been used to maintain life in this renal failure state. However, dialysis imposes a heavy mental and physical burden on patients and their families, as well as on medical economics. According to the statistics of the Japan Society for Dialysis Therapy in 2018, the number of dialysis patients in Japan is about 340,000, and about 40,000 patients with end-stage renal disease are newly starting dialysis treatment every year. As a result, this dialysis medical cost amounts to 1.6 trillion yen annually, accounting for 4% of the total medical cost, putting pressure on the Japanese medical economy. Furthermore, dialysis is a symptomatic treatment, and once introduced, it must be continued for a lifetime.

For these reasons, measures to maintain and prevent deterioration of renal function are major issues, and prevention and control of metabolic syndrome and development of measures to prevent deterioration of renal function due to aging are becoming urgent issues. This gradual increase in dialysis patients is not limited to Japan, but has become a global trend due to metabolic syndrome and the aging of the global population, but so far, it is an effective “direct” treatment for renal dysfunction. There is no "medical treatment", and only "indirect therapy" such as diet therapy (restriction of intake of protein, salt, potassium, etc.) such as control of the underlying disease, metabolic syndrome, avoids or delays the introduction of dialysis. However, the creation of "direct therapy" that works on the kidney itself to stop the progression of dysfunction and further improve it has become one of the major social issues, not just medical treatment.

On the other hand, 1,5-anhydrofructose (hereinafter, sometimes referred to as "1,5-AF") is a monosaccharide that is presumed to be produced in the liver by the action of lyase on starch in the living body. be. In vitro, it can be produced by allowing α-1,4-glucan lyase, an enzyme derived from certain ascomycetes and red algae, to act on starch or starch decomposition products.

Conventionally, various uses of 1,5-AF are known. For example, Patent Document 1 contains an antitumor agent containing 1,5-AF and / or its dehydrated product, ascopyrone, and Patent Document 2 contains 1,5-AF as an active ingredient. Card protein (ASC) function inhibitors and therapeutic agents for ASC-related diseases or symptoms, as well as inframasome pathway inhibitors and inframasome pathway-related diseases or symptoms containing 1,5-AF as an active ingredient. Patent Document 3 discloses a cell aging inhibitor containing 1,5-AF as an active ingredient.

Further, in Patent Document 4, 1,5-anhydroglucitol (hereinafter, sometimes referred to as "1,5-AG"), which is a metabolite of 1,5-AF, activates nitric oxide synthase. Discloses that by increasing nitric oxide production, it protects blood vessels and is effective in the treatment and prevention of ischemic diseases.

Although there are few reports on the physiological functionality of 1,5-AG, it has been reported that it has an insulin secretory action from pancreatic Langerhans islet β cells (Non-Patent Document 1).

However, the relationship between 1,5-AF and 1,5-AG and renal function has not been reported so far.

International Publication No. 2005/040147 International Publication No. 2015/016178 Japanese Unexamined Patent Publication No. 2017-128550 Japanese Unexamined Patent Publication No. 200-100601

Biochimica et Biophysica Acta 1623 (2003) 82-87

An object of the present invention is to provide a new use of 1,5-AF and its metabolite 1,5-AG.

As a result of diligent research to solve the above problems, the present inventors directly act on the kidneys of 1,5-AF and its metabolite 1,5-AG to prevent deterioration of renal function. We have found improvement and have completed the present invention.

That is, the gist of the present invention is as follows.
(1) A composition for improving renal function containing 1,5-anhydrofructose and / or 1,5-anhydroglucitol as an active ingredient.
(2) The composition for improving renal function according to (1) above, which is used for the prevention or treatment of renal failure.
(3) The composition for improving renal function according to (1) or (2) above, which is a pharmaceutical composition or a food composition.

According to the present invention, renal function can be improved and various renal dysfunctions can be treated or prevented.

FIG. 1 is a diagram showing the state of the kidneys of the control group (left) and the adenine-administered group (right) when a rat showing a renal failure image was created by oral administration of adenine. FIG. 2 is a diagram showing the measurement results of serum creatinine levels in renal failure model rats. FIG. 3 is a diagram showing the measurement results of serum urea nitrogen (BUN) in a renal failure model rat. FIG. 4 is a diagram showing the measurement results of serum phosphorus in a rat model of renal failure. FIG. 5 is a diagram showing the measurement results of serum uric acid in a renal failure model rat. FIG. 6 is a diagram showing the measurement results of serum calcium in a rat model of renal failure. FIG. 7 is a diagram showing a pathological image of the kidney in a renal failure model rat. FIG. 8 is a diagram showing the measurement results of blood 1,5-AG concentration in a renal failure model rat.

Hereinafter, the present invention will be described in detail.
The composition for improving renal function of the present invention can improve renal function and treat or prevent various renal dysfunctions.

In the present invention, renal dysfunction refers to a state caused by acute nephritis or chronic nephritis, diabetes, gout, side effects of drugs, etc., and having symptoms such as deterioration of renal filtration function and abnormal body circulation. Specific examples include glomerulonephritis (acute glomerulonephritis, rapidly progressive glomerulonephritis, chronic glomerulonephritis, membranous proliferative glomerulonephritis), chronic nephritis, secondary (secondary) nephritis, nephrosis. Syndrome, urinary poisoning, renal failure (acute renal failure, chronic renal failure), diabetic nephropathy, hypertensive nephropathy (nephrosclerosis), glomerulonephritis, glomerulonephritis, interstitial nephritis, nephrosclerosis, multiple cysts Kidney, kidney stones (urinary tract stones, kidney stones), kidney tumors (renal cell cancer, renal pelvis cancer), autoimmune diseases (systemic erythematosus, etc.) and nephritis (lupus nephritis) associated with drug administration such as anticancer drugs Obstacles can be mentioned.

1,5-AF, which is an active ingredient in the composition for improving renal function of the present invention, is described in, for example, JP-A-9-505988 (“α-1,4 for preparing 1,5-D-anhydrofructose”). -It can be prepared according to a known method such as the method described in "Use of glucan lyase").

1,5-AG can be prepared according to a known method such as the method described in Japanese Patent No. 5075376 (“Method for producing 1,5-D-anhydroglucitol”).

Since the composition for improving renal function of the present invention is stable and does not undergo any further changes, in addition to the active ingredients 1,5-AF and / or 1,5-AG, for example, a pharmaceutical carrier, an excipient, etc. It is also possible to add other formulations and products such as water-soluble agents and stabilizers.

Further, the composition for improving renal function of the present invention can be used as a pharmaceutical product, a quasi-drug, a health food, a food for specified health use, a food with a functional claim, or can be blended in foods and drinks.

The composition for improving renal function of the present invention can be administered by various methods known per se depending on its dosage form, and the dose, administration site, administration interval, period and the like can be determined by the patient. It can be appropriately determined in consideration of age, weight, medical condition, or when used in combination with other drugs or treatment methods. The administration method is not particularly limited, and examples thereof include oral administration, injection, intravenous drip infusion, and local administration in the form of spray, ointment, or the like.

The dose of the composition for improving renal function of the present invention varies depending on the dosage form, administration method, or symptom to be treated, and is, for example, the active ingredient (1,5-AF) as the dose per 1 kg of the patient's body weight. And / or 1,5-AG) can be 1 to 500 mg, preferably 10 to 100 mg, once or several times a day, continuous infusion, etc., and even once every few days. It can be administered at an appropriate administration frequency.

The dosage form of the composition for improving renal function of the present invention includes, for example, powders, granules, fine granules, capsules (for example, capsules containing powder), tablets, liquids, injections, infusions, sprays, ointments. Agents and the like can be mentioned, but are not particularly limited.

This specification includes the contents described in the specification and drawings of Japanese Patent Application No. 2020-155273, which is the basis of the priority of the present application.

Hereinafter, the present invention will be described in more detail using examples, but the technical scope of the present invention is not limited to these examples.

(Example 1) Verification of renal function improving effect of 1,5-AF / 1,5-AG by animal experiments As described below, the present inventors allowed lyase derived from seaweed (Ogonori) to act on sweet potato starch. 1,5-AF produced in the above, and 1,5-AG produced in the body by oral ingestion of 1,5-AF were evoked by administration of adenin in an "experimental renal failure model" (hereinafter, "Adenin"). It was discovered that it prevents or alleviates the pathological condition of renal failure caused by "nephropathy"). In the following experiments, 1,5-AF, or 1,5-AG metabolically converted from 1,5-AF in the body, acts directly on the kidney to prevent or reduce renal dysfunction in renal failure. It proves to be effective. That is, it is proved that 1,5-AF and 1,5-AG can be a powerful measure that can reduce or suppress the progression of renal failure in humans and, as a result, prevent or delay the introduction of dialysis. Is what you do.

1. 1. Adenine nephropathy model Adenine is one of the five types of bases that make up nucleic acids, and is one of the purine compounds that are widely present in the body. Since it is poorly soluble in water, when it is orally administered in a certain amount or more, it crystallizes and accumulates in the kidney, eventually causing renal failure, so-called uremia, so it is widely used as a typical experimental renal failure model. The present inventors have also achieved results in the pathophysiology of renal dysfunction with this model (Oyama Y., et al., Lab Invest, (2010) 90 (6): 853-66). This model is considered to be close to the model of hyperuricemia nephropathy and renal failure in human clinical practice.

The present inventors have now verified using the nephropathy model that the above-mentioned monosaccharides; 1,5-AF and 1,5-AG improve the pathological condition of renal failure in the nephropathy model rat. Yeah.

2. 2. Pathophysiology of adenine nephropathy model and pathological improvement effect by 1,5-AF Oyama Y., et al., Lab Invest, (2010) 90 (6): 853-66 Typical by oral administration of adenine according to the method described. A rat showing a typical renal failure image was created (Fig. 1).

Compared to the control group (left), the kidneys of the adenine-administered group (right) were swollen and white. The renal weight of the adenine-administered group was about twice that of the control group (control group average: 650 g, adenine group average: 1360 g).

Therefore, the effect of 1,5-AF (provided by Sunus Co., Ltd.) in this nephropathy model rat was investigated.

The rats were divided into two groups, an adenine alone-administered group and an adenine + 1,5-AF-administered group. In addition to 10 g / day of a 0.75% adenine-containing diet, 1,5-AF 200 mg / day was orally administered. Then, on the 14th day, blood was collected and the kidney was removed, and biochemical and pathological analysis was performed.

As a result, serum creatinine level (Fig. 2), serum urea nitrogen (BUN) (Fig. 3), serum phosphorus (Fig. 4), serum uric acid (Fig. 5) increased, and serum calcium (Fig. 6) decreased, which are typical. It was possible to significantly correct the metabolic abnormality of renal failure and electrolyte metabolism.

Furthermore, in the pathological image of the kidney, infiltration of inflammatory cells and reduction of fibrosis were observed in the group administered with 1,5-AF as compared with the group administered with adenine alone (Fig. 7).

In the adenine-only group, renal swelling and changes in color tone were remarkable (a-1), whereas in the 1,5-AF combination group, the thickness including the cortex and the white change were relatively maintained (a-1). FIG. 7, a-2).

Infiltration of inflammatory cells (purple) is stronger in the adenine-only administration group (b-1) than in the 1,5-AF administration group (b-2).

The presence of dilated tubules (*) (c-1) and interstitial fibrosis (arrow) (lower left of c-1) were conspicuous in the adenine-only group, but they were alleviated in the 1,5-AF group. (C-2) (HE staining).

Moreover, when the blood 1,5-AG concentration of the rat to which 1,5-AF was administered was measured, a significant increase was observed in the 1,5-AF-administered group as compared with the adenine-only-administered group (Fig. 8). ..

These data clearly show that in addition to 1,5-AF, its metabolite 1,5-AG brought about a functional and pathologically improving effect on the pathophysiology of "adenine nephropathy". It is a thing. From the above, we were able to obtain evidence that 1,5-AF and 1,5-AG alleviate the pathophysiology of renal failure and uremia.

3. 3. Discussion Renal failure is also known as "uremia", and "uremic toxin" that should be excreted from the kidneys, that is, metabolites, waste products such as urea nitrogen and uric acid, accumulate in the body and become an electrolyte. It is the final stage of kidney disease that causes serious complications such as imbalance / abnormality, encephalopathy, uremia, and arteriosclerosis, and leads to death.

Currently, this condition is being treated with an artificial kidney, that is, dialysis. However, the time and social constraints of patients in dialysis medical treatment, as well as the financial burden, have become serious problems. Furthermore, with the advent of an aging society and the increase in metabolic syndrome, the number of [renal failure → dialysis patients] is steadily increasing, and new measures are being sought.

In the course of a series of studies on the in vivo monosaccharide 1,5-AF and its metabolite 1,5-AG, we found that 1,5-AF only stopped the progression of renal damage or the kidney. It was discovered that the pathology of the insufficiency itself can be alleviated or ameliorated. 1,5-AF is a monosaccharide produced from starch in the body, which quickly becomes 1,5-AG, is excreted from the kidneys, and has no side effects. Therefore, progression of nephritis, treatment of renal failure, and avoidance of dialysis It can be a promising drug for improving the condition of the disease.

4. Conclusion 1,5-AF is a rare sugar in vivo, and the present inventors have confirmed its safety, but this monosaccharide and its metabolite 1,5-AG improve the pathophysiology of renal failure. , It has been shown to be effective in alleviating symptoms, and it is considered to present effective treatment measures for renal disorders. Until now, no drug or treatment method has been known that can alleviate the pathophysiology of nephritis and nephropathy and directly control the progression to renal failure, with 1,5-AF and 1,5-AG being the first. It is thought to have a great impact on the therapeutic science of kidney disease.

All publications, patents and patent applications cited in this specification shall be incorporated herein by reference as they are.

Claims (3)

A composition for improving renal function containing 1,5-anhydrofructose and / or 1,5-anhydroglucitol as an active ingredient. The composition for improving renal function according to claim 1, which is used for the prevention or treatment of renal failure. The composition for improving renal function according to claim 1 or 2, which is a pharmaceutical composition or a food composition.

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