Pharmaceutical composition containing cerium compound containing trivalent cerium as active ingredient

Abstract

The first problem of the present invention is to provide a novel pharmaceutical composition containing a cerium compound as an active ingredient. Furthermore, a second problem of the present invention is to provide a pharmaceutical composition for improving renal function, in particular, a pharmaceutical composition for reducing or maintaining a detection value of at least one substance selected from the group consisting of serum creatinine (CRE), blood urea nitrogen (BUN), and serum phosphorus (IP), or suppressing an increase in the detection value of at least one substance selected from the group consisting of serum creatinine (CRE), blood urea nitrogen (BUN), and serum phosphorus (IP). The present invention for solving the problem is a pharmaceutical composition containing, as an active ingredient, a cerium compound containing trivalent cerium.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions using cerium compounds containing trivalent cerium as active ingredients.

[0002] In addition, the present invention also relates to a drug for improving renal function, particularly a drug for improving renal function that reduces, maintains or inhibits the rise of at least one of serum creatinine (CRE), blood urea nitrogen (BUN) or blood phosphorus (IP). Background Technology

[0003] Kidney disease is a condition in which damage to the glomeruli and tubules of the kidneys leads to a decline in kidney function, and it has various types. As a condition, if kidney disease continues to progress, kidney function will decline and eventually lead to kidney failure. Kidney failure includes acute kidney failure, in which kidney function declines rapidly, and chronic kidney failure, in which kidney function deteriorates over a long period of time. In acute kidney failure, if the cause of the kidney function deterioration can be ruled out, there is a possibility of recovery. However, in chronic kidney failure, there is almost no hope of recovering the kidney function lost due to the progression of kidney failure.

[0004] The period when uremic symptoms appear due to the accumulation of uremic toxins in the body caused by chronic renal failure, but before the need for dialysis, is called the conservative treatment period for renal failure. During this period, blood pressure is managed with antihypertensive drugs; dietary therapy is implemented by restricting fluid intake and limiting protein, phosphorus, and potassium intake; and symptomatic medications are used to slow the progression of renal failure.

[0005] If kidney function declines further after conservative treatment for kidney failure, it will progress to end-stage renal failure (dialysis stage). End-stage renal failure requires treatment to remove accumulated waste products from the body. As a symptomatic treatment, artificial dialysis (peritoneal dialysis or hemodialysis) is necessary; as a radical cure, kidney transplantation (deceased donor kidney transplantation or living donor kidney transplantation) is required.

[0006] In 2002, the United States defined all chronic kidney diseases as chronic kidney disease (CKD). Chronic kidney disease (CKD) is not only a risk factor for developing end-stage renal failure, but also a risk factor for cardiovascular disease.

[0007] To improve chronic kidney disease (CKD), antihypertensive drugs, diuretics, insulin preparations, statins, fibrates, small intestinal cholesterol transport inhibitors, erythropoietin preparations, acidosis treatment agents, phosphate binders, vitamin D3 preparations, potassium adsorbents, activated charcoal preparations, steroids / immunosuppressants, and traditional Chinese medicine are used, depending on the cause of kidney failure and the patient's condition.

[0008] However, these are not direct ways to improve kidney function. They are symptomatic and adjunctive treatments aimed at slowing disease progression and preventing complications. There are currently no drugs that can cure chronic kidney disease (CKD).

[0009] International Patent Publication No. 2022 / 014122 discloses a pharmaceutical composition containing a cerium compound as an active ingredient, in which cerium oxide microparticles can reduce the concentrations of serum creatinine (CRE), blood urea nitrogen (BUN), and blood phosphorus (IP) in a nephropathy model system without increasing the blood concentration of alanine aminotransferase (ALT), thus being effective as a drug for improving renal function (Patent Document 1).

[0010] Incidentally, cerium nitrate, as a type of cerium salt, such as in combination with silver sulfadiazine, is used as a topical treatment for burns in Belgium, the Netherlands, France, Spain, and the United Kingdom.

[0011] The effectiveness of cerium oxalate in the indication of "hyperemesis gravidarum and nausea and vomiting caused by motion sickness" has been confirmed, but its effect as a drug to improve renal function has not been shown.

[0012] Furthermore, in Japan, because there are other suitable drugs or treatments, it was determined that "there is no basis to show effectiveness."

[0013] Existing technical documents

[0014] Patent documents

[0015] Patent Document 1: International Publication No. 2022 / 014122 Summary of the Invention

[0016] The problem that the invention aims to solve

[0017] As mentioned above, in pharmaceutical compositions in which cerium compounds are active ingredients, cerium oxide is an example of a component that demonstrates improved renal function in representative test values ​​such as serum creatinine (CRE), blood urea nitrogen (BUN), or blood phosphorus (IP) used to evaluate renal function in vivo. However, for cerium oxide, there are challenges regarding its stability during manufacturing and its stability over time in order to improve its ability to improve renal function and stabilize the properties of the particles.

[0018] Furthermore, the efficacy of cerium nitrate and cerium oxalate as drugs to improve kidney function is still unclear.

[0019] In view of the above, the first objective of the present invention is to provide a novel pharmaceutical composition comprising a cerium compound as an active ingredient.

[0020] Furthermore, a second objective of the present invention is to provide a pharmaceutical composition for improving renal function, particularly a pharmaceutical composition for reducing, maintaining, or inhibiting the rise of at least one of serum creatinine (CRE), blood urea nitrogen (BUN), or serum phosphorus (IP).

[0021] Furthermore, a third objective of the present invention is to provide a pharmaceutical composition for reducing, maintaining, or inhibiting the rise of uremic toxins in the blood.

[0022] Methods for solving problems

[0023] The present invention, which solves the above-mentioned problems, is a pharmaceutical composition using a cerium compound containing trivalent cerium as the active ingredient.

[0024] In a preferred embodiment of the invention, the pharmaceutical composition is used to improve renal function.

[0025] In a preferred embodiment of the present invention, the cerium compound is one or more selected from cerium chloride, cerium nitrate, cerium acetate and their hydrates.

[0026] In a preferred embodiment of the invention, the pharmaceutical composition of the invention comprises cerium oxide.

[0027] In a preferred embodiment of the invention, the pharmaceutical composition is used to reduce, maintain, or inhibit the rise of at least one of serum creatinine (CRE), blood urea nitrogen (BUN), or blood phosphorus (IP).

[0028] In a preferred embodiment of the invention, the pharmaceutical composition of the invention is used to reduce, maintain, or inhibit the rise of uremic toxin concentration.

[0029] In a preferred embodiment of the invention, the uremic toxin is uremic toxin in the blood.

[0030] In a preferred embodiment of the present invention, the uremic toxin is selected from one or more of indophenol sulfate, p-cresol sulfate, phenylsulfuric acid, and trimethylamine N-oxide (TMAO).

[0031] In a preferred embodiment of the present invention, the cerium compound is an ionic compound.

[0032] In a preferred embodiment of the present invention, the cerium compound is one or more selected from cerium chloride, cerium nitrate, cerium acetate, cerium citrate, and their hydrates.

[0033] In a preferred embodiment of the invention, the pharmaceutical composition is used to improve renal function and / or to treat, inhibit, or improve uremia.

[0034] In a preferred embodiment of the invention, the pharmaceutical composition of the invention is absorbable through the digestive tract.

[0035] The present invention described above, by having cerium, as an active ingredient, absorbed from the digestive tract, exerts excellent effects on reducing serum creatinine (CRE), blood urea nitrogen (BUN), and / or serum phosphorus (IP) levels, and / or reducing uremic toxin levels.

[0036] Furthermore, the present invention for solving the above-mentioned problems is as follows.

[0037] [1] A pharmaceutical composition, wherein a cerium compound containing trivalent cerium is used as the active ingredient.

[0038] [2] According to the pharmaceutical composition of [1], the cerium compound is an ionic compound.

[0039] [3] The pharmaceutical composition according to [1] or [2] is used to improve renal function and / or to treat, inhibit or improve uremia.

[0040] [4] In any one of [1] to [3], the cerium compound is one or more selected from cerium chloride, cerium acetate, cerium nitrate and their hydrates.

[0041] [5] The pharmaceutical composition according to any one of [1] to [4] contains cerium oxide.

[0042] [6] The pharmaceutical composition according to any one of [1] to [5] is used to reduce, maintain or inhibit the rise of at least one of serum creatinine (CRE), blood urea nitrogen (BUN) or blood phosphorus (IP).

[0043] [7] The pharmaceutical composition according to any one of [1] to [6] is used to reduce, maintain or inhibit the rise of uremic toxin concentration.

[0044] [8] According to the pharmaceutical composition described in [7], the uremic toxin is uremic toxin in the blood.

[0045] [9] In the pharmaceutical composition according to [7] or [8], the uremic toxin is selected from one or more of indophenol sulfate, p-cresol sulfate, phenylsulfuric acid and trimethylamine N-oxide (TMAO).

[0046]

[10] The pharmaceutical composition according to any one of [1] to [9] is absorbable in the digestive tract.

[0047] Furthermore, the present invention can be implemented in the following manner. Additionally, the preferred manner is as described above.

[0048] (1) Use of cerium compounds containing trivalent cerium in the manufacture of pharmaceutical compositions for improving renal function and / or treating, inhibiting or improving uremia.

[0049] (2) The use of cerium compounds containing trivalent cerium as effective ingredients for improving renal function and / or treating, inhibiting or improving uremia.

[0050] (3) Cerium compounds containing trivalent cerium, used to improve renal function and / or treat, inhibit or improve uremia.

[0051] (4) Methods for improving renal function and / or for treating, inhibiting or improving uremia, including administering a cerium compound containing trivalent cerium to a subject who requires improved renal function and / or treatment, inhibition or improvement of uremia.

[0052] The effects of the invention

[0053] The pharmaceutical composition of the present invention, which contains a cerium compound containing trivalent cerium as an active ingredient, is effective in reducing, maintaining, or inhibiting the rise of values ​​such as serum creatinine (CRE), blood urea nitrogen (BUN), and / or blood phosphorus (IP), which are indicators used to evaluate renal function.

[0054] Furthermore, the pharmaceutical compositions of the present invention, which contain cerium compounds containing trivalent cerium as active ingredients, are effective in reducing, maintaining, or inhibiting the rise of uremic toxins in the body, particularly in the blood. Attached Figure Description

[0055] Figure 1 This graph shows the serum creatinine (CRE) concentrations when fed a normal diet (control), an adenine-rich diet (total cerium content = 0 mmol / 100g diet), and an adenine + cerium oxide dispersion diet. It indicates that the CRE value decreases depending on the total cerium content (mol) in 100g of diet.

[0056] Figure 2 This graph shows the blood urea nitrogen (BUN) concentrations when fed a normal diet (control), an adenine-rich diet (total cerium content = 0 mmol / 100g diet), and an adenine + cerium oxide dispersion diet. It indicates that the BUN value decreases depending on the total cerium content (mol) in 100g of diet.

[0057] Figure 3 This represents the serum phosphorus concentration (IP) when fed a normal diet (control), an adenine-rich diet (total cerium content = 0 mmol / 100g diet), and an adenine + cerium oxide dispersion diet. The IP value decreases as it depends on the total cerium content (mol) in 100g of diet.

[0058] Figure 4This graph shows the alanine aminotransferase (ALT) concentrations when fed normal feed (control), adenine feed (total cerium content = 0 mmol / 100g feed), and adenine + cerium oxide dispersion feed. It also shows the relationship between total cerium content (mol) in 100g feed and ALT.

[0059] Figure 5 This graph shows the serum creatinine (CRE) concentrations when fed a normal diet (control), an adenine diet (CeCl3 = 0 mmol / 100g diet), and an adenine + cerium chloride diet. It indicates that the CRE value decreases depending on the amount of cerium chloride (mol) in 100g of diet.

[0060] Figure 6 This graph shows the blood urea nitrogen (BUN) concentrations when fed normal feed (control), adenine feed (CeCl3 = 0 mmol / 100g feed), and adenine + cerium chloride feed. It indicates that the BUN value decreases depending on the amount of cerium chloride (mol) in 100g of feed.

[0061] Figure 7 This represents the blood phosphorus concentration (IP) when fed normal feed (control), adenine feed (CeCl3 = 0 mmol / 100g feed), and adenine + cerium chloride feed. The IP value decreases as it depends on the amount of cerium chloride (mol) in 100g of feed.

[0062] Figure 8 This graph shows the alanine aminotransferase (ALT) concentrations when fed normal feed (control), adenine feed (CeCl3 = 0 mmol / 100g feed), and adenine + cerium chloride feed. It also shows the relationship between the amount of cerium chloride (mol) in 100g feed and ALT levels.

[0063] Figure 9 This is a graph that normalizes the average serum creatinine concentration (CRE) of the adenine-fed group to 100, while also recording the serum creatinine concentration (CRE) per mole of cerium in the total cerium dispersion and per mole of cerium in CeCl3.

[0064] Figure 10 This is a graph that normalizes the average blood urea nitrogen (BUN) concentration of the adenine-fed group to 100, while also recording the total molar amount of cerium in the cerium oxide dispersion and the blood urea nitrogen (BUN) concentration per molar amount of cerium in CeCl3.

[0065] Figure 11 This is a graph that normalizes the average blood phosphorus concentration (IP) of the adenine-fed group to 100, while recording the total molar amount of cerium in the cerium oxide dispersion and the blood phosphorus concentration (IP) per molar amount of cerium in CeCl3.

[0066] Figure 12 This is a graph that normalizes the average alanine aminotransferase (ALT) concentration of the adenine-fed group to 100, while also recording the total molar amount of cerium in the cerium oxide dispersion and the alanine aminotransferase (ALT) concentration per molar amount of cerium in CeCl3.

[0067] Figure 13 This graph shows the concentration of indophenol sulfate in plasma when fed normal feed (control), adenine feed (total cerium content = 0 mmol / 100g feed), and adenine + cerium oxide dispersion feed. It indicates that the concentration of indophenol sulfate in plasma decreases as a function of the total cerium content (mol) in 100g feed.

[0068] Figure 14 This graph shows the concentration of p-cresol sulfate in plasma when fed normal feed (control), adenine feed (total cerium content = 0 mmol / 100g feed), and adenine + cerium oxide dispersion feed. It indicates that the concentration of p-cresol sulfate in plasma decreases depending on the total cerium content (mol) in 100g feed.

[0069] Figure 15 This represents the concentration of plasma phenylsulfate when fed normal feed (control), adenine feed (total cerium content = 0 mmol / 100g feed), and adenine + cerium oxide dispersion feed. The concentration of plasma phenylsulfate decreases depending on the total cerium content (mol) in 100g feed.

[0070] Figure 16 This represents the concentration of plasma trimethylamine N-oxide (TMAO) when fed normal feed (control), adenine feed (total cerium content = 0 mmol / 100g feed), and adenine + cerium oxide dispersion feed. It indicates that the plasma trimethylamine N-oxide (TMAO) concentration decreases depending on the total cerium content (mol) in 100g feed.

[0071] Figure 17 This graph shows the amount of cerium measured in the liver when fed a cerium oxide dispersion diet and a mixture of adenine and cerium chloride. It indicates that when fed a mixture of adenine and cerium chloride, the amount of cerium measured in the liver increases depending on the total cerium content (mol) in 100g of feed.

[0072] Figure 18 This graph shows the amount of cerium measured in the kidneys when the animal is fed a cerium oxide dispersion diet and a mixture of adenine and cerium chloride. It indicates that when fed a mixture of adenine and cerium chloride, the amount of cerium measured in the kidneys increases depending on the total cerium content (mol) in 100g of feed.

[0073] Figure 19 This graph represents the concentration of indophenol sulfate in whole blood when fed normal feed (control), adenine feed (total cerium content = 0 mmol / 100g feed), and a mixture of adenine and cerium chloride feed.

[0074] Figure 20 This is a diagram showing the appearance of artificial gastric fluid with added cerium chloride, cerium nitrate, cerium acetate, or cerium oxide dispersions to adjust the total cerium content in the liquid to 0.05 M.

[0075] Figure 21 This is a graph showing the absorption spectrum of artificial gastric fluid with added cerium chloride, cerium nitrate, cerium acetate, or cerium oxide dispersion to adjust the total cerium content in the liquid to 0.05 M. Detailed Implementation

[0076] The preferred embodiments of the present invention will now be described in detail. However, the present invention is not limited to the following embodiments, and modifications can be freely made within the scope of the present invention.

[0077] The pharmaceutical composition of the present invention comprises a cerium compound containing trivalent cerium as an active ingredient. Here, the pharmaceutical composition of the present invention includes not only the form in which the cerium compound itself functions as an active ingredient, but also the form in which trivalent cerium ions released from the cerium compound function as an active ingredient.

[0078] (1) Cerium compounds

[0079] The cerium compounds of the present invention are preferably metal salts or complexes containing trivalent cerium, and their hydrates. Examples include: cerium(III) nitrate, cerium(III) chloride, cerium(III) bromide, cerium(III) iodide, cerium(III) perchlorate, cerium(III) iodate, cerium(III) sulfate, cerium(III) carbonate, cerium(III) phosphate, ceriumammonium nitrate (III), cerium(III) formate, cerium(III) acetate, cerium(III) propionate, cerium(III) butyrate, cerium(III) valerate, cerium(III) hexanoate, cerium(III) octanoate, cerium(III) oleate, cerium(III) lactate, cerium(III) citrate, cerium(III) oxalate, cerium(III) phosphate, cerium(III)-EDTA complexes, and their hydrates.

[0080] These cerium compounds can be used alone or in combination of two or more.

[0081] In a preferred embodiment of the present invention, the cerium compound of the present invention is an ionic compound. Examples of preferred ionic compounds include the above-described trivalent cerium metal salts and their hydrates.

[0082] The ionic compounds of the present invention dissolve in the digestive tract after ingestion and are absorbed in the body through the digestive tract, thereby exerting their effects as a treatment for kidney disease and reducing uremic toxins.

[0083] In addition, in this invention, "inside the body" refers to the interior of the body through the digestive tract wall, while the outside of the digestive tract wall (the space surrounded by the digestive tract wall) is the outside of the body.

[0084] As the cerium compound used in this invention, one or more selected from cerium(III) chloride, cerium(III) nitrate, cerium(III) acetate, and their hydrates are preferred. Specifically, preferred examples include: anhydrous cerium(III) chloride or its hydrates (monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, or decahydrate) with hydration levels rounded to one decimal place; anhydrous cerium(III) nitrate or its hydrates (dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, or dodecahydrate); anhydrous cerium(III) acetate or its hydrates (monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, or hexahydrate), etc. In this invention, cerium(III) hexahydrate, heptahydrate, or octahydrate is preferred, and cerium(III) heptahydrate is more preferred. Furthermore, it is preferred to use anhydrous cerium(III) acetate or its hydrated form.

[0085] The cerium compound used in this invention may also be one or more selected from cerium chloride (III), cerium nitrate (III), cerium acetate (III), cerium citrate (III), and their hydrates.

[0086] The content of the cerium compound as an active ingredient in this invention is preferably 0.001 to 100% by mass, more preferably 0.003 to 99% by mass, and even more preferably 0.01 to 98% by mass, relative to the total amount of the pharmaceutical composition of this invention.

[0087] (2) Other ingredients

[0088] In addition to cerium compounds containing trivalent cerium, the pharmaceutical compositions of the present invention may, as needed, contain additives that can be added to the pharmaceutical product, within the scope necessary to achieve the objectives of the present invention.

[0089] The pharmaceutical composition of the present invention may be in the form of cerium oxide and its hydrate.

[0090] The cerium oxide of the present invention can be either cerium oxide (III) or cerium oxide (IV), but is preferably cerium oxide (IV).

[0091] Cerium oxide is preferably in particle form, more preferably in microparticle form. The average primary particle size is 100 nm or less, preferably 50 nm or less, more preferably 20 nm or less, further preferably 10 nm or less, and most preferably 5 nm or less.

[0092] By using the small particle size of cerium oxide, the total surface area of ​​the particles, i.e. the interaction area with the adsorbed substances and other target substances, can be ensured to be large, thus enabling the preparation of drug compositions with superior effects.

[0093] Here, an electron microscope can be used to capture images of the particles, and the average diameter of any 10 or more particles in the captured image can be measured as the average first-order particle size. Alternatively, it can be done by analyzing the scattering spectrum using dynamic light scattering methods, but in this case, corrections are required through electron microscope observation.

[0094] The cerium oxide that can be added to the pharmaceutical composition of the present invention is preferably coated with a dispersant.

[0095] By coating cerium oxide particles with a dispersant, the aggregation between cerium oxide particles can be suppressed. As a result, a larger total surface area of ​​the particles, i.e., the interaction area with the target substance such as the adsorbate, can be ensured, enabling the formulation of drug compositions with superior efficacy.

[0096] Examples of dispersants used for coating cerium oxide include: sodium acetate, ammonium acetate, sodium propionate, ammonium propionate, sodium octanoate, ammonium octanoate, lysine, histidine, proline, threonine, isoleucine, alanine, leucine, glycine, valine, methionine, serine, tyrosine, glutamine, asparagine, cysteine, 3-aminopropionic acid, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, EDTA derivatives, succinic acid, lactic acid, citric acid, oleic acid, metaphosphoric acid, and their salts.

[0097] One or more of the above-mentioned dispersants can be used in combination.

[0098] The amount of dispersant coating cerium oxide that can be added to the pharmaceutical composition of the present invention is, in molar ratio to cerium oxide, 1:0.001 to 1:10, preferably 1:0.01 to 1:5, and more preferably 1:0.02 to 1:2.

[0099] When using two or more dispersants, preferably, the total amount of dispersants and the molar ratio of cerium oxide content are within the above-mentioned range.

[0100] The cerium oxide used in this invention is preferably in the form of a cerium oxide dispersion dispersed in a substrate such as water. The cerium oxide aqueous dispersion can be manufactured by the method described in International Publication No. 2022 / 014122.

[0101] In addition, as any component that can be added to the pharmaceutical composition of the present invention, one or any two or more of the following components may be added: complexing agents, excipients, lubricants, flow aids, binders, disintegrants, stabilizers, preservatives, buffers, flavoring agents, sweeteners, suspending agents, emulsifiers, flavoring agents, solubilizers, colorants, thickeners, various nutrients, vitamins, antioxidants, etc.

[0102] For example, the following can be added: sodium acetate, ammonium acetate, sodium propionate, ammonium propionate, sodium octanoate, ammonium octanoate, lysine, histidine, proline, threonine, isoleucine, alanine, leucine, glycine, valine, methionine, serine, tyrosine, glutamine, asparagine, cysteine, 3-aminopropionic acid, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, EDTA derivatives, succinic acid, lactic acid, citric acid, oleic acid, metaphosphoric acid, ascorbic acid, malic acid, tartaric acid, glucuronic acid, gallic acid, glyceric acid, hydroxybutyric acid, glyoxylic acid, and their salts; lactose; crystalline cellulose; starch; agar; gelatin; dry syrup; sugars (monosaccharides, disaccharides, oligosaccharides, or polysaccharides); electrolytes; dietary fiber, etc.

[0103] Furthermore, the pH of the aqueous dispersion or aqueous solubility of the pharmaceutical composition of the present invention is preferably 1 to 10, more preferably 2 to 9, and even more preferably 3 to 8.

[0104] (3) Dosage form

[0105] As a dosage form, the pharmaceutical composition of the present invention can be used as an oral, injectable, or topical preparation.

[0106] Oral dosage forms include tablets (including tablets with ordinary coating, sugar-coated tablets, sublingual tablets, and oral tablets), capsules, granules, powders, fine granules, syrups (including dry syrups), enteric-coated tablets (including enteric-coated capsules), sustained-release capsules, soluble film-coated tablets (including rice capsules), chewable tablets, drops, pills, oral liquids (including all oral liquid dosage forms), lozenges (lozenges, throat lozenges, etc.), sustained-release tablets, and sustained-release granules.

[0107] As injectable preparations, those that dissolve upon use can be listed, as well as those containing central venous nutrition solutions.

[0108] Examples of topical medications include loose powders, lotions, ointments / creams, shampoos, sprays (excluding inhalers), topical liquids (including liniments), patches (including pastes), aerosols (measured-dose inhalers), ear drops, eye drops, ophthalmic ointments, nasal drops (including nasal sprays), mouthwashes, rectal suppositories, inserts (vaginal suppositories, vaginal tablets, etc.), enemas, gels, and peritoneal dialysis solutions.

[0109] In addition, the pharmaceutical compositions of the present invention can also be used in infusion formulations and pharmaceutical delivery system (DDS) formulations.

[0110] There are no particular limitations on the packaging of the pharmaceutical compositions of the present invention, as long as the quality of the pharmaceutical composition and its proper use, as well as the safety during administration, are ensured. To verify the suitability of the selected packaging form and packaging materials, and to maintain the suitability of the pharmaceutical packaging throughout the product lifecycle, information including the manufacturing process of the packaging materials can be obtained and designed.

[0111] (4) Purpose and target population

[0112] Representative tests for assessing kidney function include serum creatinine (CRE) and blood urea nitrogen (BUN).

[0113] Creatine phosphate is an important energy source for muscle activity, and its metabolic waste product is creatinine. Creatinine is filtered by the kidneys and excreted in urine, but when kidney function declines, the unfiltered portion remains in the blood. In other words, it can be said that the higher the concentration of creatinine in the blood, the lower the kidney function.

[0114] When proteins are utilized, they produce ammonia, which is then converted into urea in the liver. Urea nitrogen is the nitrogenous component of urea in the blood. It is filtered by the kidneys and excreted in the urine. However, as kidney function declines, the unfiltered portion remains in the blood. In other words, it can be said that the higher the concentration of urea nitrogen in the blood, the lower the kidney function.

[0115] About 85% of phosphorus is found in bones, with the remainder mainly in cells. It is a substance involved in energy production and a component of important substances such as cell membranes and DNA. After being filtered by the kidneys, it is excreted in urine. However, in cases of severe kidney dysfunction, it cannot be fully excreted and remains in the blood. In other words, it can be said that the higher the concentration of phosphorus in the blood, the lower the kidney function.

[0116] Representative tests for assessing liver function include alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AST is also found in relatively large amounts in myocardium, skeletal muscle, and erythrocytes, but ALT is mainly found in the liver, making it suitable for investigating the presence and extent of liver cell damage.

[0117] Furthermore, the pharmaceutical composition of the present invention has the effect of promoting the reduction, maintenance, or inhibition of the increase of at least one of serum creatinine (CRE), blood urea nitrogen (BUN), or blood phosphorus (IP). That is, the pharmaceutical composition of the present invention can be used to improve renal function. In addition, the pharmaceutical composition of the present invention can be used to reduce, maintain, or inhibit the increase of at least one of serum creatinine (CRE), blood urea nitrogen (BUN), or blood phosphorus (IP). Furthermore, in a preferred embodiment, it has the effect of reducing, maintaining, or inhibiting the increase of all of the detected values ​​of serum creatinine (CRE), blood urea nitrogen (BUN), and blood phosphorus (IP).

[0118] Furthermore, the pharmaceutical composition of the present invention has the effect of not causing an increase in the level of alanine aminotransferase (ALT) in the blood upon administration. That is, the pharmaceutical composition of the present invention is characterized by its low likelihood of inducing a decline in liver function upon administration.

[0119] Furthermore, in this invention, the pharmaceutical composition for improving renal function is preferably a nephropathy treatment drug.

[0120] Furthermore, in this invention, nephropathy refers to a state of decreased kidney function due to kidney diseases such as acute kidney injury and chronic kidney failure. Additionally, nephropathy in this invention not only refers to diseases related to decreased kidney function, but also includes diseases of other organs incidentally caused by decreased kidney function. Examples of diseases of other organs include various diseases caused by uremic toxins, such as diseases of the heart and vascular system.

[0121] Furthermore, the treatment of kidney disease in this invention includes: inhibiting and / or preventing the decline of kidney function, maintaining kidney function, restoring or improving kidney function, preventing, inhibiting, improving or treating diseases caused by the decline of kidney function, and other treatments targeting all abnormalities caused by kidney disease.

[0122] The pharmaceutical composition of the present invention can be used as a treatment for kidney diseases. Preferred examples of kidney diseases for which the pharmaceutical composition of the present invention is applied include: chronic kidney disease (CKD), acute kidney injury (AKI), and chronic renal failure. Furthermore, the pharmaceutical composition of the present invention can be used to prevent or treat various diseases caused by excessive phosphorus intake, such as hyperphosphatemia, renal failure, and osteoporosis.

[0123] Furthermore, the pharmaceutical composition of the present invention has the effect of reducing substances that accumulate in the body due to decreased renal function. In the present invention, substances that accumulate in the body due to decreased renal function refer to substances that cause uremia symptoms (uremic toxin) and / or uremic toxin precursors. That is, the pharmaceutical composition of the present invention can be a reducing agent of uremic toxin and / or its precursors, more preferably in the form of a reducing agent of uremic toxin.

[0124] Furthermore, the pharmaceutical compositions of the present invention can be used to treat uremia. In addition, the pharmaceutical compositions of the present invention can be used to alleviate or suppress uremia symptoms.

[0125] In addition, in this invention, uremia refers to systemic changes caused by an extreme decline in kidney function, and refers to symptoms that appear when acute or chronic kidney injury develops.

[0126] Furthermore, the inventors have discovered that, as described in the examples, cerium can be absorbed in the body by administering a cerium oxide dispersion containing cerium(III) ions (trivalent cerium) and cerium oxide. Moreover, the inventors have confirmed that cerium can also be absorbed in the body by administering ionic compounds containing trivalent cerium, such as cerium chloride, and more specifically, it accumulates in organs.

[0127] That is, the pharmaceutical composition of the present invention is preferably absorbed in the body via a cerium compound in the digestive tract, thereby exerting the desired effect in the state of cerium compound and / or cerium ions.

[0128] In this invention, the digestive tract is preferably the intestine.

[0129] In this invention, digestive tract absorptive capacity refers to the absorption of active ingredients and other substances from the digestive tract into the body (mainly the blood).

[0130] In addition, the term "intestine" in this invention refers to the small intestine (jejunum, ileum, duodenum, etc.) and the large intestine (cecum, colon, rectum, etc.). Furthermore, intestinal absorptive capacity refers to the absorption of active ingredients and other substances from the intestines into the body (primarily into the bloodstream).

[0131] Furthermore, the pharmaceutical composition of the present invention is preferably processed into a form that is absorbable through the digestive tract. In the present invention, a dosage form in which cerium can exist in the digestive tract in a trivalent state is preferred. The processing form of the dosage form is not particularly limited; for example, the processing form of the oral preparation described above can be appropriately selected.

[0132] Furthermore, in a preferred embodiment, the cerium compound of the present invention exerts its effects by being absorbed from the digestive tract and transferred into the bloodstream, reaching various organs such as the kidneys.

[0133] When the pharmaceutical composition of the present invention is in a form that is absorbable in the digestive tract, the molecular weight of the cerium compound is preferably 5000 or less, more preferably 2000 or less, and even more preferably 600 or less.

[0134] Furthermore, in the above-described forms, the present invention is preferably a pharmaceutical composition that can be absorbed through the digestive tract. Preferably, the present invention can be formulated into a pharmaceutical composition that can be absorbed through the intestines.

[0135] Furthermore, in this invention, the cerium compound may be in a form that is absorbable through the digestive tract, preferably through the intestines. Additionally, in this invention, the cerium compound may be in a form that is absorbable through the digestive tract, preferably through the intestines.

[0136] In the above-described form, oral administration is preferred.

[0137] In addition, in this embodiment, the cerium absorbed from the digestive tract can be in the form of monatomic ions or in a state combined with other substances.

[0138] In this invention, "absorption" in the digestive tract and intestines includes not only the form in which components enter the body through active transport, but also the form in which components are passively transported into the body according to concentration.

[0139] In the form of a pharmaceutical composition that is absorbable through the digestive tract, the cerium compound is in a liquid-soluble dosage form, and in one example, a dosage form in which cerium can ionize in the digestive tract is preferred. That is, in this form, it may also be a form in which the cerium compound is not particle-processed, and / or a form in which sustained-release or enteric processing is not performed, such as coating.

[0140] Furthermore, the inventors have discovered that administering a cerium oxide dispersion containing a mixture of cerium(III) ions and cerium oxide reduces the amount of uremic toxins in the blood. Moreover, the inventors have confirmed that administering cerium trivalent ionic compounds such as cerium chloride also reduces the amount of uremic toxins in the blood.

[0141] That is, the pharmaceutical composition of the present invention can be used to reduce, maintain or inhibit the rise of uremic toxins in the body, and more specifically, to reduce or maintain the concentration of uremic toxins in the blood or to inhibit the rise of uremic toxins.

[0142] The mechanism of action of the pharmaceutical compositions of the present invention in reducing uremic toxins and / or their precursors is believed to be that the cerium compounds of the present invention participate in the inhibition of the formation of uremic toxins and / or their precursors. For example, examples include the forms in which the cerium compounds of the present invention containing trivalent cerium act in the decomposition or neutralization of uremic toxins or their precursors. Examples of uremic toxins and / or their precursors that are targeted include: tryptophan, kynurenine, serotonin, trypsin, indoles (indoleacetic acid, indolepropionic acid, indolelactic acid, indole, etc.), tyrosine, p-cresol, phenolic compounds, phosphatidylcholine, carnitine, trimethylamine (TMA), indolephenol, indolesulfonate, p-cresol sulfate, phenylsulfonate, and trimethylamine N-oxide (TMAO), etc.

[0143] In the pharmaceutical composition of the present invention, preferably, the uremic toxin that is reduced, maintained, or whose rise is inhibited is selected from one or more of indophenol sulfate, p-cresol sulfate, phenylsulfuric acid, and trimethylamine N-oxide (TMAO).

[0144] The mechanism of action of the pharmaceutical composition of the present invention in reducing uremic toxins and / or their precursors may also be that the cerium compounds containing trivalent cerium of the present invention exert their effects by reducing the activity (enzyme inhibition) of enzymes that metabolize food-derived components into uremic toxin precursors or uremic toxins. Examples of enzymes targeted include: tryptophan 2,3-dioxygenase (TDO), tryptophan hydroxylase (TPH), aromatic L-amino acid decarboxylase (AADC), tryptophanase, tyrosine phenol lyase (β-tyrosinase), trimethylamine lyase, hydroxylase, and sulfotransferase, etc.

[0145] Furthermore, as one embodiment of the present invention, the use of cerium compounds containing trivalent cerium in the manufacture of a pharmaceutical composition for improving renal function, preferably for treating kidney disease, can be cited. Further, it can be in the form of the use of cerium compounds containing trivalent cerium in the manufacture of a pharmaceutical composition for reducing or maintaining the detection value of at least one of serum creatinine (CRE), blood urea nitrogen (BUN), or blood phosphorus (IP), or inhibiting its rise. Additionally, it can be in the form of the use of cerium compounds containing trivalent cerium in the manufacture of a pharmaceutical composition for reducing or maintaining uremic toxins in the body, or inhibiting their rise, more preferably reducing or maintaining the concentration of uremic toxins in the blood, or inhibiting its rise.

[0146] In addition, it can also be in the form of a cerium compound containing trivalent cerium used in the manufacture of a pharmaceutical composition for treating, inhibiting or improving uremia, specifically for reducing, maintaining, preferably inhibiting the concentration of uremic toxins in the blood, or for reducing their rise.

[0147] Furthermore, as one embodiment of the present invention, the application of a cerium compound containing trivalent cerium as an effective ingredient for improving renal function, preferably for treating kidney disease, can be listed. Further, it can be in the form of an application of a cerium compound containing trivalent cerium as an effective ingredient for reducing or maintaining the detection value of at least one of serum creatinine (CRE), blood urea nitrogen (BUN), or blood phosphorus (IP), or inhibiting its rise. Additionally, it can be in the form of an application of a cerium compound containing trivalent cerium as an effective ingredient for reducing or maintaining uremic toxins in the body, or inhibiting their rise, more preferably reducing or maintaining the concentration of uremic toxins in the blood, or inhibiting their rise.

[0148] In addition, it can also be used as an effective ingredient containing trivalent cerium compounds for the treatment, inhibition or improvement of uremia, specifically for reducing or maintaining the concentration of uremic toxins, preferably in the blood, or for inhibiting their rise.

[0149] Furthermore, as one embodiment of the present invention, examples include: cerium compounds containing trivalent cerium for improving renal function, preferably for treating kidney disease. Further, these may be cerium compounds containing trivalent cerium used to reduce or maintain the detected value of at least one of serum creatinine (CRE), blood urea nitrogen (BUN), or blood phosphorus (IP), or to inhibit their rise. Additionally, these may be cerium compounds containing trivalent cerium used to reduce or maintain uremic toxins in the body, or to inhibit their rise, more preferably to reduce or maintain the concentration of uremic toxins in the blood, or to inhibit their rise.

[0150] In addition, it can also be in the form of a cerium compound containing trivalent cerium, which is used to treat, inhibit or improve uremia, specifically to reduce or maintain the concentration of uremic toxins, preferably in the blood, or to inhibit their rise.

[0151] Furthermore, as one embodiment of the present invention, examples include: a treatment method for improving renal function, comprising administering a cerium compound containing trivalent cerium to a subject requiring treatment to improve renal function. Furthermore, examples include: a treatment method for kidney disease, comprising administering a cerium compound containing trivalent cerium to a subject requiring treatment for kidney disease. Further, a treatment method for kidney disease may also include administering a cerium compound containing trivalent cerium to a subject requiring treatment to reduce, maintain, or inhibit the rise of at least one of serum creatinine (CRE), blood urea nitrogen (BUN), or blood phosphorus (IP). Furthermore, a treatment method for kidney disease may include administering a cerium compound containing trivalent cerium to a subject requiring treatment to reduce, maintain, or inhibit the rise of uremic toxins in the body, more preferably to reduce, maintain, or inhibit the rise of uremic toxin concentrations in the blood.

[0152] In addition, it can be a form of treatment for uremia, including administering a cerium compound containing trivalent cerium to a subject who needs to treat, suppress, or improve uremia. It can also be a form of method for reducing, maintaining, or inhibiting the rise of uremic toxins, including administering a cerium compound containing trivalent cerium to a subject who needs to reduce, maintain, preferably in the blood, the concentration of uremic toxins or inhibit its rise.

[0153] Adenine nephropathy models can be used as models of chronic renal failure to evaluate the pharmaceutical compositions of the present invention.

[0154] The rat adenine nephropathy model is a model that induces chronic progressive kidney injury by feeding rats adenine load. It is considered to be a good model for reflecting human chronic kidney disease (CKD) patients by adenine load alone.

[0155] Example

[0156] <Example 1> Confirmation Test of the Effectiveness of Cerium Compounds Containing Trivalent Cerium

[0157] (Example 1)

[0158] The efficacy of the cerium compound containing trivalent cerium in the pharmaceutical composition of the present invention was confirmed by feeding a rat model of adenine nephropathy with a dispersion containing cerium(III) ions as trivalent cerium and cerium oxide.

[0159] The materials, feed, and equipment used in animal experiments are as follows.

[0160] [Materials, feed, and equipment, etc.]

[0161] ● Rats: Slc: Wistar male rats, 12 weeks old, were purchased (SLC Corporation, Japan).

[0162] ●Powdered feed: AIN-93G powdered feed (Funabashi Farm Co., Ltd.)

[0163] ● Animal experimental feed: Laboratory MR standard feed (Nippon Agricultural Products Co., Ltd.)

[0164] ●Adenine: (Tokyo Chemical Industry Co., Ltd.)

[0165] ●Cerium oxide dispersion: The cerium oxide dispersion prepared in [Preparation of cerium oxide dispersion] (aqueous dispersion of 10.0% cerium oxide by mass, molar ratio of cerium oxide to cerium(III) ions = 9:1)

[0166] ●Cerium chloride (III): Cerium chloride (III) heptahydrate (Niki Corporation)

[0167] ●Water or hot water: Use water that has passed through a water purifier or boil it in a kettle.

[0168] ●Feed preparation mixer: Compact kitchen equipment MUM4415JP (Bosch Corporation)

[0169] ●Manual Sausage Machine: Sausage Machine (COM4SPORT)

[0170] ● Winged blood collection needle for animal testing: CL-4597 (Claire Co., Ltd., Japan)

[0171] [Preparation of cerium oxide dispersion]

[0172] In a reaction vessel equipped with a stirrer, an aqueous solution with a cerium concentration of 1.15 mol / L, consisting of 469.0 g of water, 229.072 g of cerium(III) heptahydrate (Niki Corporation), and 5.556 g of sodium acetate (Fujifilm Wako Pure Chemical Industries Co., Ltd.), was stirred while maintaining the temperature at 20°C.

[0173] Add 14.629 g of 35.4% hydrogen peroxide water (Fujifilm and Koichi Chemical Co., Ltd.) to the solution and stir for 5 minutes.

[0174] Further, 350.542 g of a 4 mol / L sodium hydroxide aqueous solution (Fujifilm and Kohden Chemical Co., Ltd.) was added and stirred for 5 minutes.

[0175] Then, heat the solution to 45°C over 10 minutes, maintain stirring for 60 minutes, and then cool it to room temperature.

[0176] The final solution had a cerium concentration of 0.7 mol / L.

[0177] The reaction solution was then washed / filtered and desalted to prepare an aqueous dispersion (cerium oxide dispersion, hereinafter also referred to as dispersion) with a cerium oxide concentration of 10.0% by mass and a molar ratio of cerium oxide to cerium(III) ions in the solution of 9:1. The molar ratio of cerium oxide to cerium(III) ions can be determined using inductively coupled plasma mass spectrometry (ICP-MS) or inductively coupled plasma atomic emission spectrometry (ICP-AES).

[0178] The particles were observed using a transmission electron microscope (TEM), and the average particle size of cerium oxide was 4.0 nm.

[0179] [Preparation of bait]

[0180] (1) Normal group

[0181] (i) Weigh 250g of powdered feed and mix it using kitchen equipment.

[0182] (ii) After stirring with kitchen equipment for 3 minutes, scrape off the bait adhering to the wall and stir again for 3 minutes. Then, add about 100mL of hot water evenly.

[0183] (iii) After gathering the ingredients by hand once, knead them again using kitchen equipment until they are more even.

[0184] (iv) Use a sausage machine to shape the kneaded bait into sticks.

[0185] (v) Cut off the shaped bait and shape it into a cylinder with a diameter of about 2.5cm and a thickness of about 1.5cm.

[0186] (vi) Dry the formed cylindrical bait in an incubator at 38°C for 2 days.

[0187] (vii) Measure the weight and calculate the percentage of residual moisture, and dry to below 10%.

[0188] (ⅷ) Place the prepared bait in a zip-locked bag and refrigerate.

[0189] Repeat steps (i) to (vi) as many times as required to prepare the special food.

[0190] (2) Adenine group

[0191] Special foods are prepared by changing (ii) used in the normal group to the following.

[0192] (ii)(Ade): While stirring, add 0.625g of adenine in small amounts several times, then stir for 3 minutes using kitchen equipment, scrape off the bait on the wall, and stir again for 3 minutes. Next, add about 100mL of hot water evenly.

[0193] (3-1) Adenine + cerium oxide dispersion (A) group

[0194] Special foods were prepared by changing (i) and (ii) of the adenine group in (2) above to the following.

[0195] (i) (Ade+ Dispersion (A)): Weigh 246.1g of powdered feed and mix it using kitchen equipment.

[0196] (ii) (Ade+ Dispersion (A)): While stirring, add 0.625g of adenine in small amounts several times, then stir with kitchen equipment for 3 minutes, scrape off the bait on the wall, and stir again for 3 minutes. Next, while stirring, add 32.7g of cerium oxide dispersion in small amounts several times, then stir with kitchen equipment for 3 minutes, scrape off the bait on the wall, and stir again for 3 minutes. Finally, add approximately 70mL of hot water evenly.

[0197] (3-2) Adenine + cerium oxide dispersion (B group)

[0198] Special foods were prepared by changing (i) and (ii) of the adenine group to the following.

[0199] (i) (Ade+ Dispersion (B)): Weigh 240.1g of powdered feed and mix it using kitchen equipment.

[0200] (ii) (Ade+ Dispersion (B)): While stirring, add 0.625g of adenine in small amounts several times, then stir with kitchen equipment for 3 minutes, scrape off the bait on the wall, and stir again for 3 minutes. Next, while stirring, add 98.2g of cerium oxide dispersion in small amounts several times, then stir with kitchen equipment for 3 minutes, scrape off the bait on the wall, and stir again for 3 minutes. Finally, add approximately 12mL of hot water evenly.

[0201] [Rat feeding]

[0202] (1) The weight of the rats was measured and divided into 4 groups.

[0203] (2) Each group was allowed free access to food and water, and the feed was adapted to the standard feed for feeding. The room temperature was 22±2℃, and the lighting was on for 12 hours a day.

[0204] (3) After acclimatization, feed them with special food and allow them free access to water. The conditions in the rearing room are the same as during acclimatization, with a room temperature of 22±2℃ and lighting for 12 hours a day.

[0205] (4) On days 0, 7, 14, 21 and 28, the animals were kept in blood collection / metabolism cages for 24 hours.

[0206] During day 0, the animals were fed standard laboratory MR feed, followed by a special diet. Feed intake, water intake, urine output, and fecal output were measured, and urine and feces were collected as samples.

[0207] (5) Remove the animal from the metabolic cage and measure its weight. After the weight measurement, collect blood using a winged lancet. The blood volume is approximately 500 μL. After culturing the blood at room temperature for 1 hour, centrifuge (1700×G, 20 min) to obtain serum.

[0208] Afterwards, the feeding of (4) metabolic cages and (5) weight measurement / blood collection were repeated.

[0209] (6) On the final 28th day, after a 1-day fast, the autopsy was performed. The autopsy was performed under anesthesia by opening the abdomen, collecting blood from the inferior vena cava, and then euthanizing the animal by exsanguination. The blood obtained was cultured at room temperature for 1 hour and then centrifuged (1700×G, 20 min) to obtain serum. In addition, whole blood supplemented with heparin was collected, centrifuged (1700×G, 20 min) to obtain plasma.

[0210] Then, the liver, kidneys, spleen, small intestine, and stomach of the euthanized rats were collected by bloodletting. The small intestine and stomach were cut open and their contents removed, and the rats were washed twice with PBS.

[0211] The analysis of the collected blood samples was entrusted to Oriental Yeast Industry Co., Ltd.

[0212] The analytical methods and reagents used for each test item are described below.

[0213] [Analysis of blood samples]

[0214] ● Serum creatinine (CRE): Enzymatic method, L-type Wako CRE·M (Fujifilm Wako Pure Chemicals Co., Ltd.)

[0215] ●Blood urea nitrogen (BUN): Urease-GLDH method, reagent manufactured by Orient Yeast Industry Co., Ltd.

[0216] ● Serum phosphorus (IP): Enzymatic method, protamine LIP II (Hitachi Chemical Diagnostics Co., Ltd.)

[0217] ●Alanine aminotransferase (ALT): JSCC standardized correspondence method, L-type Wako ALT·J2 (Fujifilm Wako Pure Chemical Industries, Ltd.)

[0218] Serum albumin (ALB): BCG method, albumin II HA-assay (Wako, Fujifilm Wako Pure Chemical Industries Co., Ltd.)

[0219] The above items were measured using a Hitachi 7180 automatic analysis device.

[0220] A graph is plotted with the measured values ​​of serum creatinine (CRE), blood urea nitrogen (BUN), and serum phosphorus (IP) or alanine aminotransferase (ALT) from blood samples collected during dissection on the ordinate, and the total molar amount of cerium in 100g of feed on the x-axis. (The graph is then divided into sections...) Figures 1-4 The Chinese side indicated that...

[0221] It was confirmed that, compared to the normal group fed the same diet as the normal group, the adenine group (total cerium concentration 0 mmol / 100g) fed the same diet as the adenine group had elevated levels of CRE, BUN, and IP, indicating decreased renal function, thus confirming adenine nephropathy. However, ALT levels were found to be the same as in the normal group.

[0222] Furthermore, it was found that as the cerium oxide content in the feed increased, the values ​​of CRE, BUN, and IP decreased, and the degree of improvement in kidney function tended to increase. Regarding ALT, the deviation was larger when the cerium oxide content was high, but it hardly changed up to about 10 mmol / 100g of total cerium concentration.

[0223] The results above confirm that dispersions containing trivalent cerium (i.e., cerium(III) ions and cerium oxide are effective in assisting, maintaining, or improving renal function.

[0224] (Example 2)

[0225] The efficacy of the cerium-containing compound of the pharmaceutical composition of the present invention was confirmed by feeding adenine nephropathy model rats with cerium(III) chloride heptahydrate, which is a cerium compound containing trivalent cerium.

[0226] Instead of the adenine + cerium oxide dispersion (A) group and (3-2) adenine + cerium oxide dispersion (B) group in the preparation of bait in Example 1, the effects of cerium chloride (III) were investigated using (4-1) to (4-3) below.

[0227] (4-1) Adenine + Cerium Chloride (C) group

[0228] Special foods were prepared by changing (i) and (ii) (Ade) of the adenine group to the following.

[0229] (i)(Ade+CeCl3(C)): Weigh 248.8g of powdered feed and mix it using kitchen equipment.

[0230] (ii) (Ade + CeCl3(C)): While stirring, add 0.625g of adenine in small amounts several times, stirring for 3 minutes with kitchen equipment, scraping off the bait from the wall, and then stirring again for 3 minutes. Next, while stirring, add 10mL of an aqueous solution containing 1.79g of cerium(III) chloride heptahydrate in small amounts several times, stirring for 3 minutes with kitchen equipment, scraping off the bait from the wall, and then stirring again for 3 minutes. Finally, add approximately 90mL of hot water evenly.

[0231] (4-2) Adenine + Cerium Chloride (D) group

[0232] Special foods were prepared by changing (i) and (ii) (Ade) of the adenine group to the following.

[0233] (i)(Ade+CeCl3(D)): Weigh 247.7g of powdered feed and mix it using kitchen equipment.

[0234] (ii)(Ade + CeCl3(D)): While stirring, add 0.625g of adenine in small amounts several times. Stir for 3 minutes using kitchen equipment, then scrape off the bait from the wall surface, and stir again for 3 minutes. Next, while stirring, add 20mL of an aqueous solution containing 3.58g of cerium(III) chloride heptahydrate in small amounts several times. Stir for 3 minutes using kitchen equipment, then scrape off the bait from the wall surface, and stir again for 3 minutes. Finally, add approximately 80mL of hot water evenly.

[0235] (4-3) Adenine + Cerium Chloride (E) group

[0236] Special foods were prepared by changing (i) and (ii) (Ade) used in the adenine group to the following:

[0237] (i)(Ade+CeCl3(E)): Weigh 245.3g of powdered feed and mix it using kitchen equipment.

[0238] (ii) (Ade + CeCl3(E)): While stirring, add 0.625g of adenine in small amounts several times. Stir for 3 minutes using kitchen equipment, then scrape off the bait from the wall surface, and stir again for 3 minutes. Next, while stirring, add 40mL of an aqueous solution containing 7.17g of cerium(III) chloride heptahydrate in small amounts several times. Stir for 3 minutes using kitchen equipment, then scrape off the bait from the wall surface, and stir again for 3 minutes. Finally, add approximately 60mL of hot water evenly.

[0239] A graph is plotted with the analytical values ​​of serum creatinine (CRE), blood urea nitrogen (BUN), and serum phosphorus (IP) or alanine aminotransferase (ALT) from blood samples collected during dissection on the ordinate, and the molar amount of cerium chloride in 100g of feed on the x-axis. (The graph is then divided into sections.) Figures 5-8 The Chinese side indicated that...

[0240] Similar to Example 1, it was confirmed that the adenine group (cerium chloride concentration 0 mmol / 100g) fed the same diet as the normal group showed increased CRE, BUN, and IP levels, indicating decreased renal function, i.e., adenine nephropathy was established. Furthermore, ALT levels were the same as in the normal group.

[0241] Furthermore, it was found that as the cerium chloride content in the feed increased, the levels of CRE, BUN, and IP decreased, and the degree of improvement in renal function tended to increase. Additionally, ALT levels were found to be the same as in the normal group.

[0242] To easily understand the difference in effectiveness between cerium oxide dispersion and cerium chloride, the detection values ​​of feed containing cerium oxide dispersion and feed containing cerium chloride were standardized with the average value of the detection values ​​in their respective adenine groups set to 100. The results are as follows: Figures 9-12 As shown.

[0243] Compared to bait containing cerium oxide dispersion, bait containing cerium chloride resulted in a decrease in the detection values ​​of CRE, BUN, and IP with only a small molar amount of cerium. The use of cerium chloride is estimated to be approximately 4 to 9 times more effective than using cerium oxide dispersion. On the other hand, when using either cerium chloride or cerium oxide dispersion, ALT levels were at the same level as the normal group.

[0244] The above results indicate that cerium(III) chloride heptahydrate, used as an example of a cerium compound containing trivalent cerium in the pharmaceutical composition of the present invention, has the effect of assisting, maintaining, or improving renal function. Furthermore, it suggests that the ability of cerium(III) chloride heptahydrate to assist renal function is greater than that of cerium oxide dispersion.

[0245] Therefore, the medicine of the present invention, which uses a cerium compound containing trivalent cerium as an active ingredient, can be used to reduce or maintain the detected values ​​of serum creatinine (CRE), blood urea nitrogen (BUN), and serum phosphorus (IP) or to inhibit their rise, that is, it can be used as a medicine to improve renal function and treat kidney disease.

[0246] <Experimental Example 2> Evaluation of the in vivo absorption of cerium in cerium oxide dispersion

[0247] The permeability of cerium oxide dispersion to blood was evaluated using healthy rats. Details regarding materials, feed, and equipment used in the animal experiments that were identical to those in Example 1 are omitted as appropriate.

[0248] [Preparation of cerium oxide dispersion]

[0249] The preparation of the cerium oxide dispersion was carried out in the same order as in Experimental Example 1.

[0250] [Preparation of bait]

[0251] (1) Normal group

[0252] Rats used in the normal group were fed in the same order as in Experiment 1.

[0253] (2) Cerium oxide dispersion group

[0254] Special foods were prepared by changing (i) and (ii) used in the normal group of Experiment Example 1 to the following:

[0255] (i) (Dispersion): Weigh 246.7g of powdered feed and mix it using kitchen equipment.

[0256] (ii) (Dispersion): Stir for 3 minutes using kitchen equipment, scrape off the bait adhering to the wall, and stir again for 3 minutes. Then, while stirring, add 32.7g of cerium oxide dispersion in small amounts several times, and stir again for 3 minutes using kitchen equipment, scrape off the bait adhering to the wall, and stir again for 3 minutes. Next, add approximately 70mL of hot water evenly.

[0257] [Rat feeding]

[0258] Except for measuring the weight of the rats and dividing them into two groups, the procedure was carried out in the same order as in Experiment 1.

[0259] [Analysis of cerium content in blood and organ samples]

[0260] The blood, liver, and kidney samples collected from the cerium oxide dispersion group were treated with nitric acid and aqua regia to prepare sample solutions, which were then analyzed by inductively coupled plasma mass spectrometry (Agilent 7900ICP-MS).

[0261] The results of the measurements show the cerium content per gram in blood and various organs as follows.

[0262] ● Blood <0.0020 μg Ce / g blood

[0263] ●Liver 0.71μgCe / g liver

[0264] ● Kidney 0.29μgCe / g kidney

[0265] Based on the above results, it was determined that the amount of cerium retained in the blood was trace. Calculated by organ mass, the liver and kidneys had the highest cerium content. Therefore, it is concluded that when cerium oxide dispersion is ingested, cerium is absorbed from the body through the digestive tract.

[0266] <Experimental Example 3> Effect of Cerium Oxide Dispersion on Reducing Uremic Toxins

[0267] For rats with adenine nephropathy model that were administered the cerium oxide dispersion used in Example 1 above, after performing the [rat feeding] procedure in the same way as in Example 1, the obtained plasma was used to determine the uremic toxins (indodophenol sulfate, p-cresol sulfate, phenylsulfuric acid and trimethylamine N-oxide (TMAO)) in the plasma.

[0268] The analysis of indophenol sulfate, p-cresol sulfate, phenylsulfuric acid, and trimethylamine N-oxide (TMAO) was commissioned to LSIMedience Co., Ltd.

[0269] The following is a record of the analytical apparatus used in each test project.

[0270] ●Indophenol sulfate, p-cresol sulfate, phenylsulfuric acid: LCMS-8050 manufactured by Shimadzu Corporation.

[0271] ● Trimethylamine N-oxide (TMAO): Agilent Technologies, Inc. Agilent 6545Q-TOF LC / MS.

[0272] A graph is plotted with the concentrations of indophenol sulfate, p-cresol sulfate, phenylsulfonate, and trimethylamine N-oxide (TMAO) in blood samples collected during dissection in plasma as the ordinate, and the total molar amount of cerium in 100g of feed as the abscissa. (The graph is then used to illustrate the different concentrations of these substances.) Figures 13-16 The Chinese side indicated that...

[0273] It was confirmed that, compared with the normal group fed the same diet as the normal group, the adenine group fed the same diet as the adenine group (total cerium concentration 0 mmol / 100 g) had increased concentrations of indophenol sulfate, p-cresol sulfate, phenylsulfuric acid, and trimethylamine N-oxide (TMAO).

[0274] Furthermore, it was found that as the total cerium content in the feed increased, the concentrations of indophenol sulfate, p-cresol sulfate, phenylsulfuric acid, and trimethylamine N-oxide (TMAO) all showed a decreasing trend.

[0275] The above results confirm that the cerium oxide dispersion is effective in reducing uremic toxins in the blood. Based on these results, it can be said that the pharmaceutical composition of the present invention can be used to reduce, maintain, or inhibit the rise of uremic toxins in the blood, that is, it can be used as a uremic toxin reducing agent. Moreover, it can be determined that the cerium oxide and / or trivalent cerium ions contained in the cerium oxide dispersion contribute to reducing uremic toxins in the blood.

[0276] Furthermore, based on the results of Experiments 2 and 3, it is speculated that the cerium contained in the cerium oxide dispersion, through absorption in the body, reduces the amount of uremic toxins in the blood of the subjects who were given the cerium oxide dispersion.

[0277] <Experimental Example 4> Evaluation of the in vivo absorption of cerium in cerium chloride

[0278] For the adenine nephropathy model rats used in Example 2 above, after performing the [rat feeding] procedure in the same way as in Example 2, the in vivo absorption of cerium chloride was evaluated.

[0279] The specific order is the same as that for the cerium content analysis of the organ samples in Experiment Example 2.

[0280] The results of the measurements show the cerium content per gram in blood and various organs as follows (see also reference). Figures 17-18 ).

[0281] (1) Total cerium content: When feeding a mixed feed containing cerium chloride equivalent to 1.9 mmol / 100g.

[0282] ■ Liver 2.04μgCe / g Liver

[0283] ■ Kidney 0.35μgCe / g kidney

[0284] (2) Total cerium content: When feeding a mixed feed containing cerium chloride equivalent to 3.9 mmol / 100g.

[0285] ■ Liver 4.14μgCe / g Liver

[0286] ■ Kidney 1.25μgCe / g kidney

[0287] The above results indicate that when cerium chloride is ingested, cerium is absorbed by the body and transferred to the liver and kidneys. Furthermore, the results show that cerium content is highest in the liver and kidneys, and that the amount of cerium in organs increases with the concentration of cerium chloride. Therefore, it is concluded that when cerium chloride is ingested, cerium is absorbed from the digestive tract (intestines, etc.).

[0288] Furthermore, compared to Experiment 2 (when a cerium oxide dispersion was mixed to achieve a total cerium content of 72.2 mmol per 100 g of feed and fed), the amount of cerium accumulated in organs increased after ingestion of cerium chloride. This result indicates that, compared to cerium oxide, ionic compounds containing trivalent cerium, such as cerium chloride, are absorbed more cerium from the body.

[0289] <Experimental Example 5> The effect of cerium chloride on reducing uremic toxins

[0290] For the adenine nephropathy model rats used in Example 2 above, after performing the [rat feeding] procedure in the same way as in Example 2, the uremic toxin (indodophenol sulfate) in the whole blood was determined.

[0291] The specific order is as follows.

[0292] [Deproteinization of whole blood]

[0293] In a 1.5 mL polypropylene test tube, a precipitation solvent (5.56 μmol / L 2-naphthalenesulfonic acid-acetonitrile solution) and a blood sample (whole blood) were mixed. After standing at room temperature, solid-liquid separation was performed by centrifugation to obtain the supernatant. A 10 mmol / L ammonium acetate aqueous solution was added to the supernatant, followed by centrifugation to obtain the final supernatant. Through these steps, the blood sample was diluted 50-fold, and the final concentration of 2-naphthalenesulfonic acid was 1 μmol / L.

[0294] [HPLC determination]

[0295] A blood sample of 2.5 μL was obtained by injecting the sample using an automated sampler. The components that absorb light at 280 nm were detected by ultraviolet-visible spectrophotometry (UV-VIS) under the following measurement conditions.

[0296] ● Column: CEPCELL PAK MADE HR S5 (2.1×150mm, Osaka Soda)

[0297] ● Column oven temperature: 40℃

[0298] ●Mobile phase: 10 mol / L ammonium acetate / acetonitrile = 80 / 20

[0299] ●Flow rate: 100μL / minute

[0300] A graph with the concentration of indophenol sulfate in blood samples collected during dissection as the ordinate and the total molar amount of cerium in 100g of feed as the abscissa is plotted in... Figure 19The study confirmed that, compared to the normal group fed the same diet as the normal group, the concentration of indophenol sulfate increased in the adenine group fed the same diet as the adenine group (total cerium concentration 0 mmol / 100 g). Furthermore, the concentration of indophenol sulfate tended to decrease when ingested with cerium chloride in conjunction with adenine.

[0301] Based on the above results, it can be said that the pharmaceutical composition of the present invention containing ionic compounds of trivalent cerium such as cerium chloride can be used for the purpose of reducing, maintaining or inhibiting the rise of uremic toxins in the blood, that is, it can be used as a uremic toxin reducing agent.

[0302] <Example 6> Confirmation Test on the Solubility of Cerium Compounds in Artificial Gastric Fluid

[0303] In the trivalent cerium of the pharmaceutical composition of the present invention, the dissolution of cerium chloride, cerium nitrate, and cerium acetate, which are ionic compounds, in a solution conceived as gastric juice (artificial gastric juice) was confirmed. As the artificial gastric juice, it was prepared and used according to the disintegration test solution 1 described in the dissolution test method of the Japanese Pharmacopoeia using a method equivalent to that of the Pharmacopoeia. The specific order is as follows.

[0304] [Materials and equipment, etc.]

[0305] ●Cerium (III) chloride: Nikki Co., Ltd.

[0306] ●Cerium (III) nitrate: Nikki Co., Ltd.

[0307] ●Cerium (Ⅲ) acetate: Nikki Co., Ltd.

[0308] ●Cerium oxide dispersion: Prepared in the same order as in Experimental Example 1.

[0309] ●Sodium chloride: Tomita Pharmaceutical Co., Ltd.

[0310] ● Hydrochloric acid (35.0~37.0%): Kanto Chemical Co., Ltd.

[0311] ●Taiwanese pH meter: Horiba Seisakusho Co., Ltd.

[0312] Volumetric flask (10mL, 100mL): Shibata Science Co., Ltd.

[0313] ● Quartz cuvettes for spectrophotometers (optical path length: 10mm, optical path width: 10mm): Azov Corporation

[0314] ● Spectrophotometer: A&E La(UK) Ltd.

[0315] [Preparation of artificial gastric juice]

[0316] Add approximately 50 mL of purified water to a volumetric flask (100 mL), then add 8.26 g of hydrochloric acid and 2.00 g of sodium chloride. Add purified water to the mark on the volumetric flask, stir thoroughly, and prepare a total of 100 mL of aqueous solution. By diluting this aqueous solution 10 times, an artificial gastric fluid (1000 mL, pH: approximately 1.2) equivalent to the first solution in the disintegration test was prepared.

[0317] [Preparation of the test sample]

[0318] Cerium chloride, cerium nitrate, or cerium acetate were dissolved in artificial gastric fluid to a concentration of 0.05 M. Specifically, 0.19 g of cerium chloride, 0.22 g of cerium nitrate, and 0.18 g of cerium acetate were added to artificial gastric fluid to a total volume of 10 mL. The resulting mixture was poured and stirred at room temperature for approximately 1 hour, and used as the test sample.

[0319] A comparative example was also conducted by adding a cerium oxide dispersion to simulated gastric fluid. In the preparation of the comparative example, the cerium oxide dispersion was first diluted with simulated gastric fluid to a total cerium concentration of 0.05 M. Specifically, 0.86 g of cerium oxide dispersion was added to simulated gastric fluid, bringing the total volume to 10 mL. The resulting mixture was poured and stirred at room temperature for approximately 1 hour, and used as the test sample.

[0320] [Absorbance Confirmation]

[0321] Each sample was placed in a quartz cuvette for a spectrophotometer, and the absorbance at 200–600 nm was measured using an absorbance spectrophotometer.

[0322] Figure 20 and Figure 21 The results show the appearance of the test samples and the absorbance of each sample. When cerium chloride, cerium nitrate, or cerium acetate was added to the artificial gastric fluid, all test samples were visually confirmed to be transparent liquids without any precipitation. When measuring the absorbance of each test sample, no absorbance beyond 340 nm was detected; only specific absorption was observed in the ultraviolet region around 200–340 nm.

[0323] This indicates that cerium chloride, cerium nitrate, and cerium acetate dissolve in gastric juices and exhibit similar solubility.

[0324] On the other hand, when the cerium oxide dispersion was added to the artificial gastric fluid, the resulting test sample was a fluorescent yellow liquid, and no precipitation was observed visually. When the absorbance of this test sample was measured, it exhibited absorption over a relatively large range including 200–600 nm.

[0325] This indicates that cerium oxide dispersions exhibit different solubility compared to ionic compounds containing trivalent cerium, such as cerium chloride.

[0326] The results show that cerium chloride (III), cerium nitrate (III), and cerium acetate (III) are soluble in gastric juice, and their solubility is similar. On the other hand, it was confirmed that the cerium oxide particles contained in the cerium oxide dispersion were not completely dissolved in strongly acidic solutions such as simulated gastric juice, but were dispersed in particle form.

[0327] The results show that among cerium compounds, ionic compounds containing trivalent cerium, such as cerium chloride, dissolve in the digestive tract, such as the stomach, and become cerium ions. Moreover, combined with the results of the in vivo absorption test in Example 4, it is believed that these ionic compounds containing trivalent cerium do not form particles with a certain particle size like cerium oxide, but rather exert their effects based on absorption in the body.

[0328] In summary, when cerium chloride, cerium nitrate, and cerium acetate are administered orally, cerium ions are absorbed into the body in some form during the digestive tract, thereby exerting their effects.

[0329] Furthermore, based on the results of Experiments 4-6, it is speculated that cerium in ionic compounds containing trivalent cerium is absorbed into the body through the digestive tract, thereby reducing the amount of uremic toxins in the blood of subjects who are given the ionic compound.

[0330] Industrial availability

[0331] This invention can be used to improve kidney function, specifically to treat, prevent, and / or inhibit the deterioration of kidney disease and its associated diseases.

Claims

1. A pharmaceutical composition, wherein a cerium compound containing trivalent cerium is used as the active ingredient.

2. The pharmaceutical composition according to claim 1, wherein the cerium compound is an ionic compound.

3. The pharmaceutical composition according to claim 1 or 2, for improving renal function and / or for treating, inhibiting or improving uremia.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cerium compound is one or more selected from cerium chloride, cerium acetate, cerium nitrate, cerium citrate and their hydrates.

5. The pharmaceutical composition according to any one of claims 1 to 4, comprising cerium oxide.

6. The pharmaceutical composition according to any one of claims 1 to 5, for reducing, maintaining, or inhibiting the rise of at least one of serum creatinine (CRE), blood urea nitrogen (BUN), or blood phosphorus (IP).

7. The pharmaceutical composition according to any one of claims 1 to 6, used to reduce, maintain or inhibit the rise of uremic toxin concentration.

8. The pharmaceutical composition according to claim 7, wherein the uremic toxin is uremic toxin in the blood.

9. The pharmaceutical composition according to claim 7 or 8, wherein the uremic toxin is selected from one or more of indophenol sulfate, p-cresol sulfate, phenylsulfuric acid, and trimethylamine N-oxide (TMAO).

10. The pharmaceutical composition according to any one of claims 1 to 9 is absorbable through the digestive tract.

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