WO2006132321A1

WO2006132321A1 - Agent for preventing, ameliorating and treating phosphorus-induced disorder, oral preparation for adsorbing phosphate ion in food, drink or drug and method of producing the same

Info

Publication number: WO2006132321A1
Application number: PCT/JP2006/311535
Authority: WO
Inventors: Hitoshi Endou; Tomotaka Yanagita; Koji Yamashita
Original assignee: J-Pharma Co., Ltd.
Priority date: 2005-06-09
Filing date: 2006-06-08
Publication date: 2006-12-14
Also published as: TW200731981A; JPWO2006132321A1; WO2006134828A1; TW200727906A

Abstract

It is intended to provide an agent for preventing, ameliorating and treating phosphorus-induced disorder and an oral preparation having a high biological safety and a high capability of adsorbing phosphorus, characterized by containing, as the active ingredient, ferric hydroxide which is produced in the presence of a ferrous species.

Description

Specification

Phosphorus disorder preventive / ameliorating agent, oral preparation for adsorbing phosphate ions in foods, drinks or medicines and method for producing them

Technical field

[0001] The present invention relates to a drug and an oral preparation capable of adsorbing phosphate ions with high efficiency, for which excessive intake is a problem. More specifically, (1) prevention, improvement or treatment of organ damage caused by phosphorus, which can improve the blood concentration of phosphorus in patients with renal failure and control the amount of phosphorus accumulated in the body, (2) food and drink, etc. The present invention relates to an oral preparation for preventing various diseases caused by phosphorus, which can solve the problem of excessive intake of powerful phosphorus.

Background art

[0002] Phosphorus is an essential substance for living bodies. Here, humans break down and absorb food into phosphate ions in the digestive tract (especially the small intestine). By the way, the daily average phosphorus intake of Japanese adults is about 10 mg. For normal people, about 80 percent of this is absorbed, and about 80 percent of the absorbed phosphorus is said to be excreted from the kidneys. However, when renal function is impaired (renal failure), the amount of phosphorus excreted decreases, resulting in an increase in serum phosphorus concentration (hyperphosphatemia). Here, the serum phosphorus concentration of healthy individuals is maintained at 0.25 to 4.5 mg / dl, and 4.5 mgZdl or more is defined as hyperphosphatemia.

[0003] This hyperphosphatemia causes abnormal calcium metabolism and increased parathyroid function, changes in bones throughout the body (renal osteodystrophy), and calcium deposition in various organs, especially It causes deposition on the heart valve 'aorta' lung, etc. (ectopic calcification). These cause fatal complications such as myocardial infarction, which only worsen the quality of life of patients with renal failure, and worsen the prognosis. Furthermore, hyperphosphatemia itself is said to be a promoting factor for kidney damage. Thus, how to maintain normal blood levels of phosphorus is an important issue in patients with renal failure.

[0004] Here, as described above, in renal failure, the absolute amount of phosphorus that can be excreted by the kidneys decreases. Therefore, in renal failure, the amount of phosphorus absorbed from the gastrointestinal tract When this kidney capacity is exceeded, phosphorus accumulates in the body. So far, from the digestive tract If the total amount of phosphorus absorbed does not exceed the capacity of the kidney, then renal failure has been treated. Specifically, in addition to dietary diets with a phosphorus-restricted diet, a phosphorus adsorbent (in the digestive tract, especially in the small intestine, adsorbs phosphate ions generated from food and excretes it as it is to reduce the amount of phosphorus absorbed. Treatment has been performed in combination with a drug that can be reduced (for example, Patent Documents 1 to 4).

[0005] However, the phosphorus adsorbents that have been used in the past and have been studied for clinical application have the following problems.

[0006] First, an aluminum preparation (hydroxyl-aluminum gel) has a strong adsorption power of phosphate ions in the digestive tract and lowers the serum phosphorus concentration, but aluminum once absorbed from the digestive tract is not excreted outside the body. In addition, aluminum poisoning due to the accumulation of aluminum in the body has become a problem (aluminum encephalopathy, aluminum osteopathy, anemia). Therefore, in Japan, the administration of aluminum preparations to dialysis patients has been contraindicated since June 1992.

[0007] Next, calcium preparations (calcium carbonate, calcium acetate, etc.) are used in place of aluminum preparations and are still widely used in Japan. In addition, it has a bad taste and is difficult to drink, and conversely, calcium is absorbed from the gastrointestinal tract, causing hypercalcemia and causing further adverse effects such as ectopic calcification.

[0008] Further, in recent years, a new substance has appeared as a phosphorus adsorbent, and its use is currently under investigation. One of them is the hydrochloride {Sevelamer Hydrochloride (trademark)} of a polymer of Probu-2-en-1-amine and 1-chloro-2,3-epoxypropane, a phosphorus-bonding polymer developed in the United States. Yes, it was approved and used in Japan in January 2003. However, this drug often requires a large dose to improve hyperphosphatemia, and in addition, there are a number of problems with gastrointestinal complications such as constipation that must be resolved. is there. The use of another lanthanum carbonate is being studied in the United States and Europe, but the effects of lanthanum on the living body have not been fully elucidated and may have the same problems as aluminum preparations. Therefore, there is a question whether it will be put to practical use.

Patent Document 1: Japanese Patent Laid-Open No. 2-77266

Patent Document 2: JP-A-3-182259 Patent Document 3: Japanese Patent Laid-Open No. 7-2903

Patent Document 4: WO0lZ66607 Publication

Disclosure of the invention

Problems to be solved by the invention

[0009] Furthermore, since 1999, various iron compounds (stabilized polynuclear iron hydroxide, iron (3) -saccharide complex,

The use of iron (3) —sucrose complex, ferric polymaltose complex, ferric citrate) as a phosphorus adsorbent has been studied. However, the iron compound has a problem that it has a low phosphate adsorption ability and must be taken in a large amount like calcium carbonate and sevelamer hydrochloride (trademark) in order to improve hyperphosphatemia. However, when the substance is applied clinically, it does not cause accumulation in the body (iron poisoning) such as aluminum gel and serious complications of extinguishers such as sevelamer hydrochloride. Therefore, the present invention pays attention to the iron compound having such advantages, and increases the adsorptivity so that the phosphate adsorption property of the iron compound is comparable to or surpassing that of the conventional adsorbent. The first object of the present invention is to provide an agent for the prevention and improvement of phosphorus disorders that has high biological safety and is not inferior in performance.

[0010] When a large amount of phosphorus-containing food or drink or a drug containing phosphate is consumed, a large amount of phosphate ions appears in the extinguisher. When a large amount of phosphoric acid produced in the gastrointestinal tract is absorbed in a large amount from the mucosa of the gastrointestinal tract and exceeds the excretion capacity of the kidney, phosphorus may accumulate in the body, resulting in the possibility of the above-mentioned phosphorus damage S There is also. Therefore, the present invention is effective for preventing various diseases in which the phosphate ions are directly or indirectly involved by adsorbing phosphate ions generated by digestion and decomposition of foods and drinks and drugs. Provides an oral preparation (for example, a food / drink additive, a food / drink additive, a drug additive, or a drug auxiliary) having an excellent biological safety and comprising an iron compound having a high phosphate-adsorbing ability as an active ingredient This is the second purpose.

Means for solving the problem

[0011] The present invention (1) is a phosphorus disorder preventing / ameliorating / treating agent characterized by containing ferric hydroxide produced under conditions where ferrous species are present.

[0012] In the present invention (2), the ferric hydroxide contains an oxidizing agent in a ferrous aqueous solution and an equivalent amount of ferrous iron After filling with a full amount, the alkali is removed and the pH at the end of the reaction is 1.5 to 5.5 (preferably 1.5 to

4.0, more preferably 2.0 to 3.5). The agent for preventing and improving phosphorus disorder according to the invention (1).

[0013] In the present invention (3), the ferric hydroxide contains an oxidizing agent in a ferrous aqueous solution and has a redox potential.

+ 100 to 400 mV (preferably [powder + 100 to 350 mV, more preferred [porp + +200 to 300 mV]) After adding so that the pH is 1.5 to 5.5 (preferably 1.5 to 4.

0, more preferably 2.0 to 3.5), and the agent for preventing and improving phosphorus damage according to the invention (1).

[0014] According to the present invention (4), after the ferric hydroxide is added to an aqueous ferrous solution in an amount less than the equivalent amount of ferrous oxide, the oxidation-reduction potential is adjusted to +100 to 400 mV. The agent for preventing and improving phosphorus damage according to the invention (1), which is produced by adding an alkali and adjusting the pH at the end of the reaction to 1.5 to 5.5.

[0015] The present invention (5) is the phosphorus disorder preventing / ameliorating / treating agent according to any one of the above inventions (2) to (4), wherein the oxidizing agent is hypochlorite.

[0016] The present invention (6) is the phosphorus disorder preventing / ameliorating / treating agent according to any one of the inventions (1) to (5), wherein the ferric hydroxide is amorphous.

[0017] The present invention (7) is the phosphoric acid disorder preventing / ameliorating therapeutic agent according to any one of the inventions (1) to (6), further comprising glycerin.

[0018] The present invention (8) is the agent for preventing and improving phosphorus disorders according to any one of the inventions (1) to (7), wherein the disorder is hyperphosphatemia.

[0019] According to the present invention (9), after adding an oxidizing agent to a ferrous aqueous solution in an amount less than an equivalent amount of ferrous iron, alkali is removed from the pH pH 5 to 5.5 (preferably 1. 5 to 4.0, more suitable [this] 2. 0 to 3.5) [Preventing and improving treatment of phosphorus disorders containing ferric hydroxide, characterized by including a step of adjusting so It is a manufacturing method of an agent.

[0020] According to the present invention (10), an oxidizing agent is added to an aqueous ferrous solution so that the redox potential is +100 to 400 mV (preferably +100 to 350 mV, more preferably +200 to 300 mV). After immunizing, remove the stress from the pHl. 5 to 5.5 (preferably [pure 1.5 to 4.0, more preferred plow 2. 0 to 3.5)] Improvement of the prevention of phosphorus disorders containing ferric hydroxide, characterized by comprising a step of adjusting A method for producing a therapeutic agent.

[0021] In the present invention (11), an oxidizing agent is added to a ferrous aqueous solution in an amount less than the equivalent of ferrous iron to reduce the acid reduction potential to +100 to 400 mV (preferably <100 +350 mV, More suitable 【this ίMA + 200-30

OmV), then add the anolekari to pHl. 5 to 5.5 (preferably 1.5 to 4.0, more preferably 2

A method for producing an agent for improving and preventing phosphorus disorders containing ferric hydroxide, comprising a step of adjusting to 0 to 3.5).

[0022] The present invention (12) is the production method of any one of the inventions (9) to (11), wherein the oxidizing agent is hypochlorite.

[0023] The present invention (13) is the production method of any one of the inventions (9) to (12), wherein the ferric hydroxide is amorphous.

[0024] The present invention (14) is the production method of any one of the inventions (9) to (13), further comprising a step of adding glycerin.

[0025] The present invention (15) further includes a step of dehydration, freeze drying or spray drying.

;) To (14), which is one of the manufacturing methods.

[0026] The present invention (16) includes the step of adding glycerin after the pH adjustment step, before the dehydration, freeze-drying or spray-drying step, or at or after the step. It is a manufacturing method.

[0027] The present invention (17) is the production method of any one of the inventions (9) to (16), wherein the disorder is hyperphosphatemia.

[0028] The present invention (18) adsorbs phosphate ions in foods and drinks or medicines, characterized by containing ferric hydroxide produced under conditions where ferrous species are present. For oral use.

[0029] According to the present invention (19), after the ferric hydroxide is added to the ferrous aqueous solution with an oxidizing agent in an amount less than the equivalent amount of ferrous iron, the alkali is removed. The process of the invention (18) produced by adjusting the pH to be 1.5 to 5.5 (preferably 1.5 to 4.0, more preferably 2.0 to 3.5). It is a mouthpiece.

[0030] According to the present invention (20), the ferric hydroxide has an oxidation-reduction potential as an oxidizing agent in a ferrous aqueous solution.

+ 100 to 400mV (preferably [tap + 100 to 350mV, more preferable [tap + 200 to 300mV)] After addition, the pH at the end of the reaction is 1.5 to 5.5 (preferably 1.5 to 4.0, more preferably 2.0 to 3.5). The oral preparation of the invention (18) produced by adjusting as described above.

[0031] According to the present invention (21), the ferric hydroxide is added with an oxidizing agent in a ferrous aqueous solution in an amount less than the equivalent amount of ferrous iron, and the oxidation-reduction potential is +100 to 400 mV (preferably + 100 to 350 mV, more preferably +200 to 300 mV), then alkali is added and the pH at the end of the reaction is 1.5 to 5.5 (preferably 1.5 to 4.0, more suitable) Is an oral preparation according to the invention (18) produced by adjusting to 2.0 to 3.5).

[0032] The present invention (22) is an oral preparation according to any one of the inventions (19) to (21), wherein the oxidizing agent is hypochlorite.

[0033] The present invention (23) is the oral preparation according to any one of the inventions (18) to (22), wherein the ferric hydroxide is amorphous.

[0034] The present invention (24) is the oral preparation according to any one of the inventions (18) to (23), further comprising glycerin.

[0035] The present invention (25) is the oral preparation according to any one of the inventions (18) to (24), which is a food / beverage product additive, a food / beverage product adjuvant, a drug additive, or a drug adjuvant.

[0036] According to the present invention (26), an oxidant is added to an aqueous ferrous solution in an amount less than the equivalent amount of ferrous iron, and then anoleic acid is removed from pHl. 5 to 5.5 (preferably 1. 5 to 4.0, more suitable [This product 2. 0 to 3.5) [Food and drink or medicine containing ferric hydroxide, characterized by including a step of adjusting to this level This is a method for producing an oral preparation for adsorbing phosphate ions in a product.

[0037] According to the present invention (27), an oxidizing agent is added to a ferrous aqueous solution so that the redox potential is +100 to 400 mV (preferably +100 to 350 mV, more preferably +200 to 300 mV). After immunizing, remove the stress from the pHl. 5 to 5.5 (preferably [pure 1.5 to 4.0, more preferred plow 2. 0 to 3.5)] It is a manufacturing method of the oral preparation for adsorbing the phosphate ion in food-drinks or a medicine containing ferric hydroxide characterized by including the process to adjust.

[0038] According to the present invention (28), an oxidizing agent is added to a ferrous aqueous solution in an amount less than the equivalent amount of ferrous iron to reduce the acid reduction potential to +100 to 400 mV (preferably [kakuma + 100 to 350 mV, After making it more suitable (koma + 200-30 OmV), pour anolecali pHl. 5 to 5.5 (preferably 1.5 to 4.0, more preferably 2 A method for producing an oral preparation for adsorbing phosphate ions in foods and drinks or medicines, comprising a step of adjusting to 0 to 3.5).

[0039] The present invention (29) is the production method according to any one of the inventions (26) to (28), wherein the oxidizing agent is hypochlorite.

[0040] The present invention (30) is the production method of any one of the inventions (26) to (29), wherein the ferric hydroxide is amorphous.

[0041] The present invention (31) is the production method of any one of the inventions (26) to (30), further comprising a step of adding glycerin.

[0042] The present invention (32) further includes a step of dehydration, freeze drying or spray drying.

6) to (31) !, one of the manufacturing methods.

[0043] The present invention (33) includes the step of adding glycerin after the pH adjustment step, before the dehydration, freeze-drying, or spray-drying step, or at or after the step. It is a manufacturing method.

[0044] The present invention (34) is the manufacturing method according to any one of the inventions (26) to (33), which is a food / beverage product additive, a food / beverage product adjuvant, a chemical additive, or a chemical adjuvant. .

[0045] Here, each term in the present specification will be explained. “Ferrous ferrous species” refers to substances in which iron is present in a divalent state, such as ferrous iron and ferrous compounds (eg, ferrous hydroxide). The “ferrous iron aqueous solution” is not particularly limited as long as it is an aqueous solution containing ferrous ions, and may contain other substances. The “oxidant” is not particularly limited, and examples thereof include hypochlorite, hydrogen peroxide, and calcium hydride peroxide, and hypochlorite is preferable. “Phosphorus disorder” refers to the fact that excessive accumulation of phosphorus in the body caused by chronic renal failure in many cases causes damage to various organs. Major diseases or symptoms include, for example, bone Dysfunction, calcium deposition in organs such as heart and arteries, anemia, secondary hyperparathyroidism. “Prevention / improvement treatment agent” refers to a drug used for at least one of prevention, improvement and treatment. The term “oral” is not particularly limited as long as it is administered orally. For example, when added to food and drink (food additive), when taken separately from food and drink (such as supplements). (Food supplements), when added to drugs (drug additives), when taken separately from drugs (drug supplements) Any of (agent) is included.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the best mode of the present invention will be described. The “treatment for improving and preventing phosphorus disorders” and “oral preparations for adsorbing phosphate ions in foods and beverages” according to the present invention have different uses (except for prevention of phosphorus disorders, Common in terms of composition), but common in composition (phosphorus adsorbent). Therefore, first, the phosphorus adsorbent will be described, and then each application will be described in detail.

[0047] The present phosphorus adsorbent includes amorphous hydroxy-ferric iron produced under conditions where ferrous species (eg, hydroxy-ferrous iron) are present. Here, the active ingredient exhibiting high phosphorus adsorption capacity is amorphous hydroxy-ferric iron, but if hydroxy-ferric iron is used, the effect is not achieved. For example, hydroxide and ferric hydroxide produced by adding caustic soda to ferric solution and commercially available hydroxide and ferric hydroxide do not show so high phosphorus adsorption capacity (see Examples). This ferric hydroxide is based on the Eh (redox potential) pH diagram in the Fe ²⁺ -Fe (OH) system.

Three

If it exists as a seed, it remains in ferrous iron, but it exists as ferric iron and is generated under extremely unstable conditions. Ferrous hydroxide contained in the sediment contains ferrous iron, and is unstable and extremely amorphous. Therefore, Fe— 0— Fe— 0— Fe bond is unstable and easy to break, and this hydrated ferric iron ferric hydroxide and ferric acid group are formed while breaking the bond. It is presumed that the reaction with ions and the like shows a remarkably high adsorption power.

[0048] Here, although the chemical structure of hydroxide-ferric iron is not certain, it is presumed that it is the following structure based on experimental results and the like (however, the hydroxide-ferric hydroxide of the present invention is However, the present invention is not limited to the estimated form). That is, the ferric hydroxide essentially contains ferric iron, and an oxygen atom or a hydroxyl group is six-coordinated to the iron atom, and the six-coordinate iron is linked through the oxygen atom. It is estimated that Then, it is presumed that a certain type of water molecule present around the iron atom is destabilizing the bond as a result of affecting the bond between the iron atom and the oxygen atom. Then, as a result of the exchange of hydroxyl groups or unstable oxygen atoms coordinated to iron atoms and ions (for example, phosphate ions) and iron atom forces S-ons (phosphate ions), Conceivable. Under this assumption, the preferred form is Fe-O-Fe-O-Fe (clusters) have a moderate size due to the presence of appropriate hydroxyl groups.

[0049] Here, in one manufacturing process of the present phosphorus adsorbent, as described below, by reacting ferrous iron with an oxidizing agent (for example, sodium hypochlorite), a hydroxyl group is formed. It has been changed to ferrous. Here, the oxidation-reduction reaction formula is shown below. In the following equation, for ease of understanding, hydroxide and ferric iron are simply expressed as “Fe (OH)”.

Three

Formula 1

[0050] _t ,

2Fe ⁺⁺ + NaC10 + 5H ₂ O——> 2Fe (OH) ₃ + NaCl + 4H ⁺

[0051] Thus, 1 mol of hypochlorous acid reacts with 2 mol of ferrous iron (that is, 1 mol of hypochlorous acid is equivalent to 2 mol of ferrous iron). Then, as explained below, in the production process, the amount of oxidizing agent used is less than the equivalent of ferrous iron (for example, less than 1 mol of hypochlorous acid in the case of 2 mol of ferrous iron). By doing so, ferrous iron is completely oxidized to ferric iron so that it can be constructed.

[0052] Here, "amorphous" or "very high degree of amorphous" means that the 20 value in the powder X-ray diffraction using Cu Κ α-ray as an X-ray source is 5 ° to 80 °. It has at least one amorphous halo figure in the range of °, which means that there is no obvious crystalline peak. In addition, a slight crystalline peak may be observed in the amorphous halo figure depending on the starting material at the time of manufacture. In such a case, powder X-ray diffraction using Cu K-wire as an X-ray source is possible. The crystallinity peak intensity observed in the range of 20 ° to 80 ° with a 20 value is 5% or less in terms of the ratio of the corresponding crystalline reference substance to the crystalline peak (% X-ray diffraction intensity Z reference substance). If it is. As a specific% X-ray diffraction intensity Z reference material, those given by the following formula in accordance with ASTM (American Society for Testing and Materials) D3906 can be used. The number of crystalline peaks used for calculating the integrated reflection intensity is not particularly limited, but a range of 1 to 8 is preferable.

Formula 2 [0053] _{(% X-} ray diffraction intensity / reference material) = {( _{S x} ) Z (S _R )} x 1 0 0 s _x : Integrated reflection intensity of the sample

s _R : Integral reflection intensity of reference material

[0054] As described above, although the active ingredient is hydroxide and ferric iron, it is unavoidable because it is produced under the condition where ferrous species (for example, ferrous hydroxide) are present as described above. Contains ferrous species. The content of ferrous ferrous species (for example, hydroxide and ferrous iron) is not particularly limited, but it is usually 5% by weight or less based on the dry weight (furnace dry, 105 ° C, 2h). Is from 0.01 to 4% by weight, more preferably from 0.1 to 2% by weight. In addition, at the time of manufacture, ferrous species are inevitably contained in this way, but the components may be removed by washing.

[0055] Furthermore, the present phosphorus adsorbent may contain crystalline hydroxy-ferric hydroxide as long as amorphous ferric hydroxide as an active ingredient is present. In this case, the amorphous component is preferably 30% or more, more preferably 50% or more, and further preferably 75% or more.

[0056] The present phosphorus adsorbent preferably further contains glycerin. Depending on the method of drying and aging (long-term storage), the ferric hydroxide hydrates dehydrates the OH groups bound to the iron of Fe—0—Fe—0—Fe, resulting in larger clusters, etc. It may change to a stable state and the adsorption power may decrease. Therefore, for example, by mixing glycerin with wet ferric hydroxide and ferric hydroxide, dehydration of OH groups is difficult to occur even when dried, so that a decrease in adsorptive power can be remarkably suppressed. Here, the content of glycerin is preferably 20% by weight or less based on the dry weight (furnace dry, 105 ° C., 2 h).

[0057] Next, a method for producing a phosphorus adsorbent according to the best mode will be described. This phosphorus adsorbent (Step 1A) contains an oxidizing agent (eg, hypochlorite aqueous solution) in an aqueous ferrous solution less than the equivalent amount of ferrous iron (preferably 0.3 to 0.95, more preferably 0.4 to 0.8), or (step 1B) an oxidizing agent (eg, hypochlorite aqueous solution) is added to the ferrous iron aqueous solution with a redox potential of +100 to 400 mV (preferably Komama + 100 to 350 mV, more suitable [Korama + 200 to 300 mV) After having been prepared, (Step 2) Remove alkali (preferably caustic) pHl. 5 to 5 .5 (preferably 1.5 to 4.0, more preferably 2.0 to 3.5). Here, the order of (Step 1A) or (Step 1B) and (Step 2) is important. A high-performance phosphorus adsorbent cannot be obtained. Hereinafter, each condition will be described.

First, the ferrous salt that can be used in the ferrous aqueous solution is not particularly limited as long as it is a water-soluble salt, and examples thereof include ferrous sulfate, ferrous chloride, and ferrous nitrate. However, ferrous sulfate is preferred because it allows easy filtration of the precipitate. Further, the concentration of ferrous ions in the ferrous aqueous solution is preferably 0.05 to 2M.

Next, the usable oxidizing agent is not particularly limited, but is preferably hypochlorite. Here, examples of the hypochlorite include sodium hypochlorite and calcium hypochlorite, and sodium hypochlorite is particularly preferable. The hypochlorite concentration in the hypochlorite aqueous solution is not particularly limited, but commercially available 5 to 10% can be used.

[0060] Here, in the case of adopting Step 1A, the amount of the oxidizing agent to be used is set to an amount that is less than the equivalent of ferrous iron in the aqueous ferrous water solution. Here, the amount of the oxidizing agent is preferably 0.3 to 0.95 force S in terms of equivalent ratio to the amount of ferrous iron, and more preferably 0.4 to 0.8.

[0061] When Step 1B is employed, an oxidizing agent (for example, a hypochlorite aqueous solution) is added to the ferrous aqueous solution, and the oxidation-reduction potential is +100 to 400 mV (preferably +100 to 350 mV, More preferably, it is added to +200 to 300 mV). At this time, it is preferable to add an oxidizing agent solution (for example, hypochlorite aqueous solution) dropwise with stirring.

[0062] It should be noted that step 1A and step 1B are not necessarily mutually independent steps, and if step 1A is performed, step 1B is eventually performed and vice versa. To do.

[0063] Next, after adding a predetermined amount of an oxidizing agent in step 1A, or after confirming that the acid reduction potential is within the above range in step 1B, step 2 of adding an alkali is performed. Do. Here, the alkali is not particularly limited, but is preferably a caustic alkali. Examples of the caustic alkali include caustic soda and caustic potassium, and caustic soda is preferable. In addition, the alkali concentration (preferably caustic concentration) is, for example, 0.5 to 5N. Then, an alkaline aqueous solution (preferably a caustic aqueous solution) is added to a solution to which a predetermined amount of oxidizing agent is added (step 1A) or a solution in which the oxidation-reduction potential is within the above range (step 1B). , Adjust to pHl. 5 to 5.5 (preferably <1.5 to 4.0, more suitable 2.0 to 3.5). By performing this operation, amorphous ferric hydroxide precipitates, The present phosphorus adsorbent can be obtained.

[0064] The present phosphorus adsorbent is preferably in a dry form for handling. Here, dehydration, freeze-drying or spray drying is preferable as the drying method. According to these methods, since the dehydration of the Fe—OH bonding force during drying is small, the phosphate adsorption power is kept high.

[0065] Further, when glycerin is mixed before drying, at the time of drying, or after drying, a decrease in phosphate adsorption power can be suppressed to a small extent. Here, the addition amount of glycerin is 20% or less (preferably 3 to 7%) with respect to the dry weight (furnace dry, 105 ° C., 2 h). The timing of mixing glycerin is not particularly limited, but is preferably after pH adjustment and before drying.

[0066] Next, uses and usage methods of the present phosphorus adsorbent will be described. The present phosphorus adsorbent is useful in various fields where excess phosphorus and biosafety are problems, such as for chronic renal failure and artificial dialysis patients. This will be specifically described below.

[0067] First, when the present phosphorus adsorbent is used as a “phosphorus disorder prevention and improvement treatment agent” (phosphorus absorption inhibitor) in patients with chronic renal failure and artificial dialysis, this agent is filled in enteric capsules and administered orally. Is considered optimal. The dosage is 1 to 5 g per day, depending on the patient's condition, especially the degree of renal failure and blood phosphorus levels. Thus, when used for patients with chronic renal failure and industrial dialysis patients, this ferric hydroxide-ferric iron binds to phosphate ions and is excreted in the stool as water-insoluble iron phosphate. become. The reaction between hydroxide and ferric ion and water-soluble phosphate is completed within 1 minute. Therefore, phosphate ions produced during the passage of food through the small intestine over 2-3 hours are adsorbed and excreted by almost 100 percent hydroxyaluminum iron. In addition, when this drug is orally administered in a practical amount, absorption of iron ions derived from the substance of the present invention is hardly considered in the digestive tract.

[0068] From the viewpoint of preventing various diseases caused by excessive intake of phosphorus, the present phosphorus adsorbent may be used as an "oral preparation". That is, when this drug is taken orally together with foods and drinks and drugs containing phosphorus, this substance adsorbs phosphoric acid generated in the intestine. As described above, this drug is extremely effective in preventing phosphorus disorders caused by a large intake of phosphate. The dose depends on the age and weight of the person to be taken and the type and amount of food and drink to be taken, but is, for example, 1 to 5 g per day. In addition, even in the form added to foods or drugs orally taken into the body (for example, additives), it is physically separated from these (for example, sublimin). G)

Example

[0069] Admission of Phosphorous Absorbing Agent (Phosphorus P

0. Add dropwise 6% sodium hypochlorite (active chlorine 5%) to 800 ml of 1M ferrous sulfate aqueous solution with stirring so that the oxidation-reduction potential is 270 mV (drop amount = 29.8 g; equivalent ratio = 0 588) and left for 3 minutes with stirring. 1N sodium hydroxide was added to the solution until the pH was stabilized at 2.7 to obtain a phosphorus adsorbent according to this example. The pH at the end of the reaction was 2.7 and the redox potential was +204 mV.

[0070] Component analysis

(l) Quantitative analysis by Fe form

The above phosphorus adsorbents were quantitatively analyzed for T-Fe, M-Fe, Fe2 ⁺ and Fe3 ⁺ (where "T" means total and "M" means metal) . For T-Fe, salt 還元 stannous reduced potassium dichromate titration, for M-Fe, mercuric chloride-dissolved potassium dichromate titration, and for Fe2 ⁺ , inert Gas-filled acid dissolution Measured by the potassium nichromate titration method, and Fe ³⁺ was calculated by the calculation method [Fe ³⁺ = T—Fe— (M—Fe + Fe ²⁺ )]. Table 1 shows the results. No. 1 is a paste-like phosphorus adsorbent, and No. 2 is a freeze-dried phosphorus adsorbent.

[0071] [Table 1]

Table 1 1 Quantitative analysis results (unit: wt «

[0072] (2) Identification of constituent phases by X-ray diffraction (XRD)

Device: Rigaku RINT-2200

Tube: Cu

Voltage current: 40kV—40mA

Scanning speed: 4. / min Scanning range: 5 ° -80 ° (2 Θ)

An X-ray diffraction test was performed under the above measurement conditions. The X-ray diffraction measurement charts are shown in Figs. 1 to 4, and the analysis results are shown in Table 2.

[0073] [Table 2]

Table 1 2 X-ray diffraction analysis results

Relative strength: + + + + very strong + + + strong ten + medium

+ Weak (+) Very weak-not detected

[0074] From the analysis results, the Ledocok mouth site (γ-FeOOH) was detected very weakly for both Sample No. 1 and No. 2. In addition, both samples were broad except for the diffraction peaks obtained in the X-ray diffraction chart, and it was found that the amorphousness was extremely high.

[0075] Phosphorus adsorption ability test

Phosphorus absorption capacity is measured by taking 0.5 g of the phosphorus adsorbent according to this example in a dry weight of 0.5 g of ammonium phosphate solution (5.9 g PZD in 20 ml) and releasing it for 24 hours with occasional shaking. This was filtered, and the phosphorus concentration of the filtrate was measured and calculated.For comparison, IN NaOH was rapidly stirred to pH 7.5 to 8.0 in 1M FeCl aqueous solution. did

Three

Adsorption ability was also tested for ferric hydroxide and hydrous ferrous hydroxide produced by dehydration of hydrous ferric hydroxide (commercially available). The results are shown in Table 3.

[0076] [Table 3]

Table 1 3

[0077] Examples of addition of glycerin, etc.

To the phosphorus adsorbent with a water content of 70% produced according to the above method, 5% by weight of each of the phosphorus adsorbents was added and lyophilized. Table 4 shows the phosphorus adsorption capacity of the dried product. [0078] [Table 4]

Table 1 4

[0079] Trial line ί (approval test of ^ .width phosphorus i ^ Rl ^ 乍 ffl using rats)

A group of 3 SD male rats (8 weeks old) were bred for 1 week by administration of this phosphorus adsorbent (phosphorus disorder preventive / ameliorating treatment) added to the diet. Blood phosphorus concentration before administration (Dayl), blood was collected 2 days after feeding (Day 3), 4 days after (Day 5), and 7 days after (Day 8), and blood phosphorus concentration was measured. The group that did not contain this phosphorus adsorbent was designated as Control, and the groups that consumed food containing 1% 3% 5% of this phosphorus adsorbent were 1% of this phosphorus adsorbent, 3% of this phosphorus adsorbent, and 5% of this phosphorus adsorbent. It is shown as% in the figure (Figure 5). In addition, a significant difference from the phosphorus concentration at each time point of Control is indicated by ** (P <0.01).

[0080] Trial, Experimental Example 2 (Phosphorus adsorption test in small intestinal fluid solid system)

In order to approximate the composition of the test solution to that of the intestinal solution, 187 g Z700 ml of an enteral nutrient one elental (manufactured by Ajinomoto Pharma Co., Ltd.) and Ringer's solution 11 adjusted to pH 7.2, which is a small intestinal fluid model, were tested. Liquid. Then, 0.178 g of phosphorus adsorbent (oral preparation) according to this example (dry weight conversion) was added to 100 ml of the test solution, and the water-soluble P concentration in the system was measured. For comparison, the same measurement was performed when no phosphorus adsorbent was added (Tests 1 and 2). Furthermore, the same measurement was performed when water-soluble phosphoric acid (the amount assuming that the total amount of organic P in the enteral nutrient was digested in the intestine) was added to the test solution ( Tests 3 and 4). The results are shown in the table. As can be seen from the table, water-soluble P was removed by this phosphorus adsorbent (oral), and when a large amount of water-soluble phosphorus was further added, the amount of phosphorus removed by this phosphorus adsorbent (oral) increased. That is, when the water-soluble phosphorus concentration was low, the amount of adsorption was small, and when it was high, the amount of adsorption was large. “Total P” in the table is the total value of water-soluble and water-insoluble phosphorus. “Water-insoluble phosphorus” refers to phosphorus that is not water-soluble, such as phosphorus in proteins.

[0081] [Table 5] Additional water-soluble P Water-soluble P Phosphorus adsorption J Total P

P removal by ppm P m ppm

1 Test solution 29.8 155.6

2 Test solution + Phosphorous adsorbent 1 21.1 8.7 155.6

3 Test solution + additional water-soluble P 155.6 185.4 ― 311.2

4 Test solution + additional water-soluble P + phosphorus adsorbent 155.6 83.7 102.7 311.2 Brief description of the drawings

[FIG. 1] FIG. 1 is an X-ray diffraction measurement chart of Sample No. 1.

FIG. 2 is an X-ray diffraction measurement chart of Sample No. 1.

FIG. 3 is an X-ray diffraction measurement chart of Sample No. 2.

FIG. 4 is an X-ray diffraction measurement chart of Sample No. 2.

[FIG. 5] FIG. 5 shows the results of Test Example 1 (the action of reducing the phosphorus concentration in blood of a phosphorus adsorbent using rats).

Claims

The scope of the claims

[I] An agent for preventing and improving phosphorus disorders, characterized by containing ferric hydroxide produced under conditions in which ferrous species are present.

[2] After the ferric hydroxide is added to the ferrous aqueous solution with an oxidizing agent in an amount less than the equivalent of ferrous iron, an alkali is added to give a pH at the end of the reaction of 1.5 to 5.5. The agent for preventing and / or improving phosphorus disorder according to claim 1, produced by adjusting so as to prevent the above.

[3] After ferric hydroxide is added to the ferrous aqueous solution with an oxidizing agent so that the redox potential is +100 to 400 mV, an alkali is added and the pH at the end of the reaction is 1.5 to 5. The agent for preventing and improving phosphorus disorder according to claim 1, wherein the agent is prepared by adjusting to 5.

[4] After the ferric hydroxide is added to the ferrous aqueous solution in an amount less than the equivalent amount of ferrous iron to reduce the oxidation-reduction potential to +100 to 400 mV, the alkali is removed and the reaction is completed. PH of 1.5

The agent for improving and preventing phosphorus disorders according to claim 1, which is produced by adjusting to ˜5.5.

[5] The therapeutic agent for improving prevention of phosphorus disorders according to any one of claims 2 to 4, wherein the oxidizing agent is hypochlorite.

[6] The treatment for improving and preventing phosphorus damage according to any one of [1] to [5], wherein the ferric hydroxide is ferric.

[7] The agent for improving and preventing phosphorus disorders according to any one of claims 1 to 6, further comprising glycerin.

[8] The agent for preventing and improving phosphorus disorder according to any one of claims 1 to 7, wherein the disorder is hyperphosphatemia.

[9] Add oxidizing agent to ferrous aqueous solution in an amount less than the equivalent of ferrous iron, and then add alkali to pHl.

A method for producing a remedy for improving and preventing phosphorus disorders containing ferric hydroxide, comprising a step of adjusting to 5 to 5.5.

[10] The method includes the step of adding an oxidizing agent to ferrous aqueous solution so that the acid-reduction potential becomes +100 to 400 mV, and then adding alkali to adjust the pH to 5 to 5.5. And a method for producing an agent for preventing and improving phosphorus disorders containing ferric hydroxide.

[II] Add an oxidizing agent to the ferrous aqueous solution in an amount less than the equivalent of ferrous iron to adjust the acid-reduction potential to +100 to 400 mV, and then add alkali to adjust the pH to 5 to 5.5. Including the process of A method for producing an agent for preventing and improving phosphorus disorders containing ferric hydroxide.

[12] The production method according to any one of claims 9 to 11, wherein the oxidizing agent is hypochlorite.

[13] The production method according to any one of claims 9 to 12, wherein the ferric hydroxide is amorphous.

[14] The production method according to any one of claims 9 to 13, further comprising a step of adding glycerin.

[15] The production method according to any one of claims 9 to 14, further comprising a step of dehydration, freeze-drying or spray-drying.

[16] The production method according to claim 15, wherein the step of adding glycerin is performed after the pH adjustment step, before the step of dehydration, freeze-drying, or spray-drying, or during or after the step.

[17] The production method according to any one of claims 9 to 16, wherein the disorder is hyperphosphatemia.

[18] characterized by containing ferric hydroxide produced under conditions in which ferrous species are present

An oral preparation for adsorbing phosphate ions in foods and drinks or medicines.

[19] After the ferric hydroxide is added to the ferrous aqueous solution with an oxidizing agent in an amount less than the equivalent of ferrous iron, the pH at the end of the reaction is 1.5 to 5.5 by adding alkali. 19. An oral preparation according to claim 18, which is produced by adjusting so as to make the preparation.

[20] After ferric hydroxide is added to the ferrous aqueous solution with an oxidizing agent so that the redox potential is +100 to 400 mV, an alkali is added and the pH at the end of the reaction is 1.5 to 5. 19. The oral preparation according to claim 18, wherein the oral preparation is adjusted to be 5.

[21] The ferric hydroxide is added with an oxidizing agent in an aqueous ferrous solution in an amount less than the equivalent of ferrous iron to reduce the oxidation-reduction potential to +100 to 400 mV, and then the alkali is removed. 19. The oral preparation according to claim 18, wherein the oral preparation is adjusted to have a pH of 1.5 to 5.5.

[22] The oral preparation according to any one of claims 19 to 21, wherein the oxidizing agent is hypochlorite.

[23] The oral preparation according to any one of claims 18 to 22, wherein the ferric hydroxide is amorphous.

[24] The oral preparation according to any one of claims 18 to 23, further comprising glycerin.

[25] The oral preparation according to any one of claims 18 to 24, which is a food / beverage product additive, a food / beverage product adjuvant, a chemical additive, or a chemical adjuvant.

[26] After adding an oxidizer to the ferrous aqueous solution in an amount less than the equivalent of ferrous iron, alkali is added and pHl.

The manufacturing method of the oral preparation for adsorbing the phosphate ion in food-drinks or a medicine containing ferric hydroxide characterized by including the process adjusted to 5-5.

[27] The method includes the step of adding an oxidizing agent to ferrous aqueous solution so that the acid-reduction potential is +100 to 400 mV, and then adding an alkali to adjust the pH to 5 to 5.5. The manufacturing method of the oral preparation for adsorbing the phosphate ion in food-drinks or a chemical | medical agent containing ferric hydroxide.

[28] Add an oxidizing agent to the ferrous aqueous solution in an amount less than the equivalent of ferrous iron to adjust the acid-reduction potential to +100 to 400 mV, and then add alkali to adjust the pH to 5 to 5.5. A method for producing an oral preparation for adsorbing phosphate ions in foods and drinks or medicines, which comprises the step of:

[29] The production method according to any one of claims 26 to 28, wherein the oxidizing agent is hypochlorite.

[30] The production method according to any one of claims 26 to 29, wherein the ferric hydroxide is amorphous.

[31] The production method according to any one of claims 26 to 30, further comprising a step of adding glycerin.

[32] The production method according to any one of claims 26 to 31, further comprising a step of dehydration, freeze-drying or spray-drying.

[33] The production method according to claim 32, wherein a step of adding glycerin is performed after the pH adjustment step, before the step of dehydration, freeze-drying or spray-drying, at the time of the step or after.

[34] The production method according to any one of claims 26 to 33, which is a food / beverage product additive, a food / beverage product supplement, a chemical additive, or a chemical supplement.