Linear saturated aliphatic dicarboxylic acid-iron (iii) complex, preparation method and application thereof

Abstract

This invention belongs to the field of phosphate binders, specifically relating to a linear saturated aliphatic dicarboxylic acid-iron(III) complex, its preparation method, and its applications, particularly its use in preparing drugs for the treatment or prevention of hyperphosphatemia. In the dicarboxylic acid-iron(III) complex, the molar ratio of iron to dicarboxylic acid is 1:0.8~1.2, and the dicarboxylic acid is a linear saturated aliphatic dicarboxylic acid. The complex is prepared by reacting a ferric salt and a dicarboxylic acid salt in a solvent. In vitro phosphate binding experiments demonstrate that the dicarboxylic acid-iron(III) complex of this invention exhibits high phosphate binding capacity per unit mass of iron within the pH range of 3-7, and maintains a high phosphate binding capacity per unit mass of iron in vivo, significantly superior to commercially available sucrose ferric hydroxide chewable tablets. As an oral phosphate binder, the complex of this invention exhibits stronger phosphate binding capacity per unit mass of iron in vivo, higher iron utilization, lower total iron intake, and fewer adverse reactions.

Description

Technical Field

[0001] This invention belongs to the field of phosphate binders, and relates to linear saturated aliphatic dicarboxylic acid-iron(III) complexes, their preparation methods, and their applications. More specifically, this invention relates to linear saturated aliphatic dicarboxylic acid-iron(III) complexes capable of binding phosphates, and their use in the preparation of drugs for treating hyperphosphatemia. Background Technology

[0002] Phosphorus is an essential mineral for the human body, participating in key physiological processes such as homeostasis, energy metabolism, bone formation, and signal transduction. Human phosphorus is mainly ingested through diet, absorbed by the intestines, and excreted by the kidneys. Hyperphosphatemia is a common complication of chronic kidney disease, especially in end-stage renal disease patients undergoing dialysis. Long-term hyperphosphatemia can lead to secondary hyperparathyroidism, bone disease, and induce vascular and soft tissue calcification, significantly increasing the risk of cardiovascular events and all-cause mortality. Clinically, hyperphosphatemia is mainly treated through diet, dialysis, and phosphate binders. However, dietary phosphorus control alone and conventional dialysis techniques are often insufficient to effectively control serum phosphorus levels in hemodialysis patients. Therefore, oral phosphate binders are necessary to reduce intestinal phosphorus absorption and achieve effective management of hyperphosphatemia.

[0003] Oral phosphate binders are highly effective drugs for the clinical treatment of hyperphosphatemia. Although traditional oral phosphate binders, such as aluminum-containing and calcium-containing phosphate binders, have good efficacy, long-term use poses safety risks: aluminum-based preparations can easily lead to the accumulation of aluminum in tissues and cause systemic toxicity, such as low-turnover bone disease, encephalopathy, or anemia; high-dose calcium-based preparations can induce hypercalcemia, excessive suppression of parathyroid hormone (PTH), and dynamic bone disease development.

[0004] Sevelamer is an anion exchange resin phosphate binder. Because it lacks phosphate binding specificity, high doses are required to control serum phosphate levels in patients with end-stage renal disease (ESRD), leading to poor patient adherence. Sevelamer carbonate tablets (Novela) ® During clinical application, there are relatively obvious adverse reactions. Among them, adverse reactions with a reported incidence rate of more than 5% include vomiting, nausea, diarrhea, indigestion, abdominal pain, flatulence, and constipation. These adverse reactions involve multiple aspects of the gastrointestinal tract and will have a certain negative impact on the patient's clinical treatment experience and treatment effect.

[0005] Lanthanum carbonate chewable tablets (Forslino) ®Lanthanum carbonate is an approved phosphate binder, but its phosphate binding efficiency is significantly dependent on the pH of the gastrointestinal tract. The optimal pH for phosphate binding is 1.5-3. As the pH increases, the phosphate binding capacity weakens, and it is difficult to dissolve above pH 6.0. The most common adverse reactions of lanthanum carbonate chewable tablets in clinical use are concentrated in the gastrointestinal tract, specifically manifesting as nausea, vomiting, and abdominal pain. These gastrointestinal reactions can easily cause discomfort to patients, and there is also a risk of long-term accumulation of lanthanum in tissues, affecting the continued use of the drug.

[0006] Sucrose ferric hydroxide chewable tablets (Vivre) ® This is a sugar-containing iron-based phosphate binder. This phosphate binder has significant gastrointestinal adverse reactions, with the main adverse reactions reported in more than 5% of cases being diarrhea, nausea, and changes in stool color. It is contraindicated in people with abnormal glucose metabolism. It also interacts with many drugs and can cause tooth discoloration with long-term use. Although the above adverse reactions do not involve symptoms that seriously endanger the patient's life, they can still reduce the patient's medication comfort and may reduce the patient's treatment compliance with long-term use.

[0007] Ferric citrate has weak phosphate binding specificity and low binding capacity, requiring higher dosages to achieve the same phosphorus-lowering effect, significantly increasing the medication burden on patients. Furthermore, the redox activity of free iron in the intestinal lumen easily triggers gastrointestinal side effects. Ferric citrate tablets (AURYXIA) ® As a commonly used clinical drug, its adverse reactions vary in the treatment of different diseases: when used to treat hyperphosphatemia in dialysis patients with chronic kidney disease, adverse reactions with a reported incidence of more than 5% mainly include diarrhea, changes in stool color, nausea, constipation, vomiting, and cough; while when used to treat iron deficiency anemia in non-dialysis patients with chronic kidney disease, adverse reactions with a reported incidence of more than 5% include changes in stool color, diarrhea, nausea, constipation, abdominal pain, and hyperkalemia.

[0008] WO2007 / 088343 discloses a phosphorus binder prepared by reacting magnesium sulfate and ferric sulfate in an alkaline solution. The product is magnesium ferric hydroxide carbonate with a hydrotalcite structure. However, it not only has a low phosphate binding capacity but also releases Mg in the stomach. 2+ It can cause adverse reactions and limit its clinical application.

[0009] WO2008096130A1 and WO2010015827A2 disclose ligand-modified polyoxy-hydroxy metal ion materials, their preparation methods, and applications. These materials can be prepared using non-stoichiometric (M...) x L y(OH)z represents a compound where M is one or more metal ions, L is one or more ligands, and the OH group plays a corresponding role depending on its form (bridging oxo groups or surface hydroxyl groups in solid oxohydroxide materials). WO201015827A2 explicitly states that ligand L can be arbitrarily substituted with oxygen or hydroxyl groups, a characteristic that directly determines that the material is a mixture with variable composition and structure. Although this material can bind phosphates, due to the variable types and compositions of ligands and metal ions, and the variable fine structure, it exhibits variable phosphorus-binding characteristics.

[0010] CN109497565B discloses a composition comprising a metal ion complexed with gum arabic or a pharmaceutically acceptable salt thereof, wherein the metal ion is Fe(II), Fe(III), or a mixture thereof, wherein the composition comprises 10% to 50% by weight of the metal ion and 50% to 90% by weight of the gum arabic, wherein the metal ion interacts with each other via oxygen atoms and / or hydroxyl groups, and although it has the ability to bind phosphates, the relationship between the composition ratio of the metal and gum arabic and the phosphate binding performance is not clearly defined.

[0011] In summary, metal-based phosphate binders are highly specific, but have a high incidence of gastrointestinal adverse reactions. Compared to lanthanum-based phosphate binders, iron-based phosphate binders are relatively safer, but the incidence of diarrhea and fecal color changes (melena) is relatively high with iron-based phosphate binders such as sucrose hydroxyl iron oxide and ferric citrate. Although sucrose hydroxyl iron oxide and ferric citrate have been shown to have phosphate-binding capacity in in vitro aqueous solutions and have been clinically proven to reduce and control blood phosphorus, the clinical adverse reactions, especially fecal color changes, suggest that these two iron-based phosphate binders have low iron-phosphate binding efficiency in the gastrointestinal tract, resulting in low iron utilization. A large amount of unbound iron may cause adverse reactions.

[0012] Currently, the rate of achieving target serum phosphorus levels among dialysis patients in my country is low. Existing phosphate binders used to treat hyperphosphatemia have poor phosphorus binding specificity, low binding capacity, or are prone to causing side effects or have long-term safety issues. Therefore, there is an urgent need to develop an iron-based phosphate binder that has high phosphate binding capacity per unit mass of iron in the gastrointestinal tract, high iron utilization rate, low total iron intake, good safety, low adverse reactions, and good compliance. Summary of the Invention

[0013] The purpose of this invention is to provide a linear saturated aliphatic dicarboxylic acid-iron(III) complex, a phosphate binder with strong phosphorus-binding capacity per unit mass of iron in vivo, for the treatment of hyperphosphatemia. In vitro phosphate binding experiments have demonstrated that the complex of this invention has a greater advantage in phosphorus binding capacity per unit mass of iron (mgP / gFe) over a wide pH range in solution compared to other disclosed iron-based materials. In particular, in vivo animal experiments have shown that the linear saturated aliphatic dicarboxylic acid-iron(III) complex of this invention has a significantly higher phosphorus-binding capacity per unit mass of iron in the gastrointestinal tract than commercially available sucrose hydroxyl iron oxide and other iron-based materials. As an oral phosphate binder, the linear saturated aliphatic dicarboxylic acid-iron(III) complex of this invention has advantages such as stronger phosphorus-binding capacity per unit mass of iron in vivo, higher iron utilization rate, lower total iron intake, and fewer adverse reactions, which helps improve compliance. Furthermore, the preparation method of the linear saturated aliphatic dicarboxylic acid-iron(III) complex of this invention is simple and stable, easily scaled up industrially, and the raw materials are widely available and inexpensive, giving it the advantage of being developed into a new generation of oral phosphate binders.

[0014] The technical solution provided by this invention is as follows:

[0015] A linear saturated aliphatic dicarboxylic acid-iron(III) complex, wherein the molar ratio of iron to linear saturated aliphatic dicarboxylic acid in the linear saturated aliphatic dicarboxylic acid-iron(III) complex is 1:0.8~1.2, the linear saturated aliphatic dicarboxylic acid-iron(III) complex is prepared by reacting a ferric salt and a linear saturated aliphatic dicarboxylic acid salt in a solvent, and the mass percentage of iron in the linear saturated aliphatic dicarboxylic acid-iron(III) complex is 20%~30%.

[0016] Furthermore, the straight-chain saturated aliphatic dicarboxylic acid contains 4 to 8 carbon atoms and has the general structural formula HOOC-(CH2). n -COOH, n=2~6.

[0017] Furthermore, the straight-chain saturated aliphatic dicarboxylic acid contains 4 to 6 carbon atoms.

[0018] Furthermore, the straight-chain saturated aliphatic dicarboxylic acid is succinic acid.

[0019] The linear saturated aliphatic dicarboxylic acid-iron(III) complex is poorly soluble in common solvents, including water, methanol, ethanol, and acetone.

[0020] The present invention also provides a method for preparing the above-mentioned straight-chain saturated aliphatic dicarboxylic acid-iron(III) complex, comprising the following steps: mixing a straight-chain saturated aliphatic dicarboxylic acid salt and a trivalent iron salt in a solvent, then stirring until the reaction is complete, separating and washing the precipitate, and drying to obtain the straight-chain saturated aliphatic dicarboxylic acid-iron(III) complex.

[0021] Further, the preparation method includes: (a) mixing a solution or suspension of a straight-chain saturated aliphatic dicarboxylate with a ferric salt solution in a stoichiometric ratio, or directly mixing a solid straight-chain saturated aliphatic dicarboxylate with a ferric salt solution in a stoichiometric ratio, or mixing a solid ferric salt with a solution or suspension of a straight-chain saturated aliphatic dicarboxylate in a stoichiometric ratio, or mixing a solid ferric salt with a solid straight-chain saturated aliphatic dicarboxylate in a stoichiometric ratio and then adding the mixture to a solvent; (b) stirring at a constant temperature until the reaction is complete; (c) cooling the reaction mixture from step (b) to room temperature; (d) separating and washing the precipitate; and (e) drying to obtain a straight-chain saturated aliphatic dicarboxylate-iron(III) complex.

[0022] Furthermore, the trivalent iron salt is selected from any one or more of ferric chloride, ferric nitrate, and ferric ammonium sulfate.

[0023] Furthermore, the straight-chain saturated aliphatic dicarboxylic acid salt is selected from any one or more of the following: alkali metal salts of straight-chain saturated aliphatic dicarboxylic acids, ammonium salts of straight-chain saturated aliphatic dicarboxylic acids, transition metal salts of straight-chain saturated aliphatic dicarboxylic acids, and rare earth salts of straight-chain saturated aliphatic dicarboxylic acids.

[0024] Furthermore, the linear saturated aliphatic dicarboxylic acid alkali metal salt is any one or more of sodium dicarboxylic acid and potassium dicarboxylic acid; the linear saturated aliphatic dicarboxylic acid alkaline earth metal salt includes any one or more of calcium dicarboxylic acid and magnesium dicarboxylic acid; the linear saturated aliphatic dicarboxylic acid ammonium salt is any one or more of ammonium dicarboxylic acid; the linear saturated aliphatic dicarboxylic acid organic amine salt includes any one or more of triethylamine dicarboxylic acid; the linear saturated aliphatic dicarboxylic acid transition metal salt is any one or more of zinc dicarboxylic acid and copper dicarboxylic acid; and the linear saturated aliphatic dicarboxylic acid rare earth salt includes any one or more of lanthanum dicarboxylic acid.

[0025] Furthermore, the preparation method of the straight-chain saturated aliphatic dicarboxylic acid salt solution / suspension is selected from the preparation method of directly dissolving or dispersing the straight-chain saturated aliphatic dicarboxylic acid salt with a solvent, or the preparation method of partially or completely neutralizing the solution / suspension containing the straight-chain saturated aliphatic dicarboxylic acid with an alkali or metal oxide; the alkali is one or more of sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium hydroxide, magnesium hydroxide, zinc hydroxide, copper hydroxide, lanthanum hydroxide, triethylamine, sodium acetate, and calcium acetate, and the metal oxide is one or more of zinc oxide, calcium oxide, and magnesium oxide.

[0026] Furthermore, the solvent is water or an aqueous organic solvent, and the solvent dissolves ferric salts.

[0027] Furthermore, the solvent is water.

[0028] Furthermore, the molar ratio of ferric salt to straight-chain saturated aliphatic dicarboxylic acid salt is 1:0.5~10.

[0029] Furthermore, the molar ratio of ferric salt to straight-chain saturated aliphatic dicarboxylic acid salt is 1:1~2.

[0030] Furthermore, the method of mixing the ferric salt solution and the straight-chain saturated aliphatic dicarboxylic acid solution / suspension is selected from adding the straight-chain saturated aliphatic dicarboxylic acid solution / suspension dropwise to the ferric salt solution, or adding the ferric salt solution dropwise to the straight-chain saturated aliphatic dicarboxylic acid solution / suspension.

[0031] Furthermore, when ferric salts react with straight-chain saturated aliphatic dicarboxylic acids in a solvent, it is not necessary to control the pH value of the reaction system.

[0032] The present invention also provides the application of the above-mentioned straight-chain saturated aliphatic dicarboxylic acid-iron(III) complex in the preparation of phosphate binders.

[0033] The present invention also provides the use of the above-mentioned linear saturated aliphatic dicarboxylic acid-iron(III) complex in the preparation of products for the treatment and / or prevention of hyperphosphatemia and complications caused by hyperphosphatemia, including soft tissue calcification, bone dystrophy, secondary hyperparathyroidism, cardiovascular disease, and pruritus.

[0034] Furthermore, the dicarboxylic acid-iron(III) complex can be used alone, or two or more of the dicarboxylic acid-iron(III) complexes can be used in combination, or it can be used in combination with other compatible active ingredients; the other compatible active ingredients include, but are not limited to, vitamins, amino acids, minerals, and other phosphorus binders.

[0035] The present invention also provides a pharmaceutical composition comprising the above-described straight-chain saturated aliphatic dicarboxylic acid-iron(III) complex.

[0036] Furthermore, the pharmaceutical composition is for oral administration.

[0037] Furthermore, the dosage form of the pharmaceutical composition includes capsules, tablets, granules, suspensions, powders, or gels.

[0038] This invention discloses a linear saturated aliphatic dicarboxylic acid-iron(III) complex that can be used to treat hyperphosphatemia. The complex is characterized by being prepared by reacting a ferric salt and a linear saturated aliphatic dicarboxylic acid salt in a solvent. The molar ratio of iron to the linear saturated aliphatic dicarboxylic acid in the complex is approximately 1:1, and the iron content in the complex is 20%–30%. The complex is sparingly soluble in common solvents such as water, methanol, ethanol, and acetone. The complex exhibits a high phosphorus binding capacity per unit mass of iron (mgP / gFe) in aqueous solution, unaffected by pH, and maintains a high phosphorus binding capacity per unit mass of iron, particularly in the animal gastrointestinal tract.

[0039] It is well known that iron-containing materials and compounds can bind to phosphates in solution. Numerous iron-containing materials, such as ferric hydroxyl oxide, ligand-modified ferric hydroxyl oxide, and iron-based metal-organic frameworks (MOFs), are used to remove phosphate ions from solution. Iron-containing compounds, such as inorganic polyferric sulfate and polyferric chloride, commonly used as flocculants in wastewater treatment, have also been proven to remove phosphates from solution. The organic iron compound ferric citrate has been developed as a pharmaceutical phosphate binder because it can bind to phosphates in solution. However, not all iron-containing substances capable of binding phosphates in solution are suitable for development as pharmaceutical phosphate binders. Different iron-containing substances have different structures, and the binding characteristics of iron to phosphates are greatly affected by their composition and structure in solutions with different pH values. In the digestive system, the pH range from gastric juice to intestinal juice is wide and the environment is complex. To bind phosphates in the gastrointestinal tract, iron-based phosphate binders need to maintain a high phosphate binding capacity across a wide pH range and minimize the release of excess unused iron. According to publicly available information, the phosphate binding capacity of ferric citrate and sucrose ferric hydroxyl oxide is significantly affected by pH value. Ferric citrate is a soluble form of iron with good solubility over a wide pH range. The optimal pH for phosphate binding is 2, and it binds almost no phosphorus in the pH range of 3-8. Sucrose ferric hydroxide also has an optimal pH for phosphate binding, but its binding capacity decreases as the pH increases. Commercially available ferric citrate tablets and sucrose ferric hydroxide chewable tablets, as phosphate binders, exhibit low iron-phosphate binding rates in the gastrointestinal tract, and higher iron intake can easily lead to adverse reactions. Therefore, ideally, iron-based phosphate binders should have a stronger phosphate binding capacity per unit mass of iron in the gastrointestinal tract.

[0040] The inventors unexpectedly discovered during experiments that mixing ferric salts and straight-chain saturated aliphatic dicarboxylic acids in solution produces a precipitate that is poorly soluble in water. The resulting precipitate not only has a high phosphorus binding capacity per unit mass of iron (mgP / gFe) in an aqueous solution in vitro within the pH range of 3-7, but also maintains a high phosphorus binding capacity per unit mass of iron in animals, which is significantly better than commercially available sucrose ferric hydroxide chewable tablets.

[0041] There are currently no reports on the direct reaction of ferric salts and straight-chain saturated aliphatic dicarboxylate salts in solvents, nor are there any reports on the composition and structure of the products resulting from the direct reaction of ferric salts and straight-chain saturated aliphatic dicarboxylate salts. The inventors systematically studied the composition and phosphorus binding characteristics of the iron complex obtained from the reaction of ferric salts and straight-chain saturated aliphatic dicarboxylate salts in solvents.

[0042] The general structural formula of the straight-chain saturated aliphatic dicarboxylic acid described in this invention is HOOC-(CH2). n-COOH. The inventors studied the reaction of straight-chain saturated aliphatic dicarboxylic acids with different carbon chain lengths and ferric salts in solution. Using sodium oxalate (n=0) and sodium malonate (n=1) with short carbon chains, no water-insoluble iron complex could be obtained regardless of the ratio of the two compounds mixed with the ferric salt solution. This may be because oxalic acid and malonic acid have a strong chelating ability and easily form soluble organic iron. Dicarboxylic acids with carbon chains containing four or more carbon atoms, such as succinic acid (n=2), glutaric acid (n=3), adipic acid (n=4), pimelic acid (n=5), octanoic acid (n=6), azelaic acid (n=7), and sebacic acid (n=8), can all be reacted with ferric salts in a solvent to obtain dicarboxylic acid-iron(III) complexes. As shown in the test results in the examples and comparative examples, the molar ratio of iron to dicarboxylic acid in these straight-chain saturated aliphatic dicarboxylic acid-iron(III) complexes is close to 1:1, and the iron content is directly related to the carbon chain length of the dicarboxylic acid. The longer the carbon chain, the lower the iron content per unit mass of dicarboxylic acid-iron(III) complex. As shown in the in vitro phosphorus binding experiment results in the examples, the linear saturated aliphatic dicarboxylic acid-iron(III) complex of the present invention exhibits a high phosphorus binding capacity per unit mass of iron within the pH range of 3-7 (greater than 500 mg P / g Fe). Almost all iron can bind with phosphate (estimated at 1 mol of iron binding to 1 mol of phosphate, 1 g of iron can bind approximately 550 mg of phosphorus). An important characteristic of the dicarboxylic acid-iron(III) complex of the present invention is that the molar ratio of iron to dicarboxylic acid in the complex is close to 1:1, and the iron content is directly related to the carbon chain length of the dicarboxylic acid. The longer the carbon chain, the lower the iron content per unit mass of the dicarboxylic acid-iron(III) complex. As shown in the comparative examples, the iron content in the azelaic acid-iron(III) complex and sebacic acid-iron(III) complex prepared according to the preparation method of the present invention is less than 20%. Although the phosphorus binding capacity (mgP / gFe) of iron per unit mass in aqueous solution is comparable for the linear saturated aliphatic dicarboxylic acid-iron(III) complex described in this invention, and is comparable for iron per unit mass in vivo, the phosphorus binding capacity (mgP / g complex) of the dicarboxylic acid-iron(III) complex is directly related to the iron content in the complex. Therefore, the azelaic acid-iron(III) complex and sebacic acid-iron(III) complex, which have longer carbon chains, do not have an advantage in phosphorus binding capacity (mgP / g complex) of the complex and are therefore not adopted. Instead, the dicarboxylic acid-iron(III) complex is prepared using linear saturated aliphatic dicarboxylic acid salts with shorter carbon chains (such as succinate, glutarate, adipate, heptanate, and octanoate).Since succinic acid has the smallest molecular weight among the dicarboxylic acids, the succinic acid-iron(III) complex prepared using only succinate has the highest iron content among similar straight-chain saturated aliphatic dicarboxylic acid-iron(III) complexes. Under the condition that the phosphorus binding amount per unit mass of iron (mgP / gFe) is equivalent, the phosphorus binding amount per unit mass of succinic acid-iron(III) complex (mgP / g complex) is the largest.

[0043] Furthermore, for comparison, the inventors prepared a fumarate-iron(III) complex. Fumarate is a rigid, four-carbon unsaturated straight-chain dicarboxylic acid. The fumarate-iron(III) complex is currently the iron-based metal-organic framework material with the highest known iron content. It has a relatively well-defined structure, rigidity, and porosity, resulting in a large specific surface area. Numerous studies have demonstrated its high phosphorus-binding capacity in solution. Test results show that the fumarate-iron(III) complex and the succinate-iron(III) complex described in this invention have comparable phosphorus-binding capacity (mgP / gFe) per unit mass of iron in aqueous solution. Surprisingly, in in vivo phosphorus-binding experiments, the fumarate-iron(III) complex exhibits significantly weaker phosphorus-binding capacity per unit mass of iron than the succinate-iron(III) complex and adipic acid-iron(III) complex described in this invention. On the one hand, this demonstrates that the linear saturated aliphatic dicarboxylic acid-iron(III) complex described in this invention has a different structure from the fumaric acid-iron(III) complex, because linear saturated aliphatic dicarboxylic acids are flexible and generally cannot form metal-organic framework structures with metal ions. It is foreseeable that other publicly known iron-based metal-organic framework materials, such as terephthalic acid-iron(III) complexes, will also have a lower phosphorus-binding capacity per unit mass of iron in animals than the linear saturated aliphatic dicarboxylic acid-iron(III) complex described in this invention. On the other hand, it also demonstrates that similar phosphorus-binding capacity per unit mass of iron (mgP / gFe) in in vitro aqueous solutions is not equivalent to similar phosphorus-binding capacity per unit mass of iron in animals. Animal experimental results demonstrate the significant advantages of the linear saturated aliphatic dicarboxylic acid-iron complex described in this invention in terms of phosphorus-binding capacity per unit mass of iron when developed into an oral iron-based phosphorus binder.

[0044] It is noteworthy that, in one embodiment, when two straight-chain saturated aliphatic dicarboxylate salts (sodium succinate and ammonium adipic acid) of different chain lengths (1:1, 3:1, 1:3) are mixed to prepare a mixed dicarboxylate-iron(III) complex, the resulting complex also exhibits a near 1:1 molar ratio of iron to total dicarboxylate, and the molar ratio of the two dicarboxylate salts in the resulting complex is close to the feed molar ratio (see specific embodiments). This indicates that the reaction between straight-chain saturated aliphatic dicarboxylate salts of different chain lengths and ferric salts in solution may occur simultaneously. Furthermore, the phosphorus binding capacity (mgP / gFe) per unit mass of iron in the mixed dicarboxylate-iron(III) complex in an in vitro aqueous solution is comparable to that of the succinate-iron(III) complex and the adipic acid-iron(III) complex prepared using a single dicarboxylate salt. When mixed dicarboxylic acid-iron(III) complexes prepared from mixed dicarboxylic acid salts (such as sodium succinate + ammonium adipate, sodium succinate + sodium glutarate + ammonium adipate) are used as oral phosphate binders, they can reduce the intake of single dicarboxylic acids in the human body and their accumulation in patients with chronic kidney disease compared to complexes prepared from single dicarboxylic acids, and may have higher safety.

[0045] It is important to note that the preparation method of phosphorus binders based on ferric hydroxide (such as sucrose ferric hydroxide) generally involves raising the pH of the inorganic iron salt solution to above pH 4 using strong or moderately strong inorganic bases such as sodium hydroxide, sodium carbonate, or sodium bicarbonate, to allow the ferric salt to fully hydrolyze and produce active ferric hydroxide precipitate. For example, the preparation method of sucrose ferric hydroxide disclosed in US6174442B1 involves first preparing ferric hydroxide by adding sodium carbonate solution to ferric chloride solution, then washing the ferric hydroxide and dispersing it in water, adding sucrose and starch as protective agents, and then rotary evaporation or spray drying to obtain sucrose ferric hydroxide; or, as disclosed in WO201015827A2, an iron-based composition for the treatment of hyperphosphatemia is obtained by mixing and dissolving carboxylic acid ligands with ferric ions in an aqueous solution with pH < 2, and then raising the pH to above 4 with an alkali to obtain ligand-modified ferric hydroxide material. However, according to the description in WO201015827A2, it is essentially a mixture. The carboxylic acid ligand is introduced into the material in a non-stoichiometric form, and may exist in the form of carboxylic acid, partial ionization, complete ionization, etc. By changing the ratio of ligand to iron during feeding and controlling different reaction pH values, materials with different composition ratios and different properties can be obtained.

[0046] The significant difference between the preparation method of the dicarboxylic acid-iron(III) complex provided by this invention and the aforementioned phosphorus binders based on ferric hydroxide is that the preparation method provided by this invention does not use any acid-base regulators such as inorganic acids (e.g., hydrochloric acid, sulfuric acid, etc.), organic acids (e.g., formic acid, acetic acid, etc.), inorganic bases or organic bases (e.g., sodium hydroxide, sodium carbonate, sodium bicarbonate, ammonia, sodium acetate, ammonium acetate, triethylamine, etc.) to adjust or control the pH. Instead, the dicarboxylic acid salt is directly mixed with the ferric salt in a solvent in the form of a solid / solution / suspension. Although the pH values ​​of the reaction solutions after mixing the ferric salt and dicarboxylic acid salt in different molar ratios are different, unexpectedly, the molar ratio of iron to dicarboxylic acid in the final product is always close to 1:1, and the phosphorus binding capacity is independent of the molar ratio of ferric salt and dicarboxylic acid salt during preparation (see specific examples). This suggests that the structure of the dicarboxylic acid-iron(III) complex prepared by this invention is significantly different from the disclosed phosphorus binders based on ferric hydroxide. The preparation method of the dicarboxylic acid-iron(III) complex provided by this invention has extremely high stability and reproducibility, and is very suitable for industrial-scale production.

[0047] According to the above preparation method of the dicarboxylic acid-iron(III) complex, the ferric salt solution in (a) can be prepared by directly dissolving commercially available iron salts such as ferric chloride, ferric nitrate, ferric sulfate, ferric ammonium sulfate, and ferric acetate in a solvent. To control the content of impurity metal elements, it can also be prepared by dissolving high-purity iron oxide in acid, or by oxidation with ferrous solution. Ferric chloride, ferric nitrate, and ferric ammonium sulfate, which are readily available, are preferred. Furthermore, the solution may contain small amounts of other organic or inorganic anions, such as acetate, formate, bromide, and perchlorate, which will not affect the formation of the dicarboxylic acid-iron(III) complex. Regardless of the iron source chosen, the molar ratio of iron to dicarboxylic acid in the final product is approximately 1:1. For pharmaceutical considerations, high-purity ferric chloride and ferric nitrate with low heavy metal content are preferred.

[0048] According to the above preparation method of the dicarboxylic acid-iron(III) complex, the dicarboxylic acid salt mentioned in (a) is an alkali metal salt of dicarboxylic acid (such as sodium dicarboxylic acid, potassium dicarboxylic acid), an alkaline earth metal salt (such as calcium dicarboxylic acid, magnesium dicarboxylic acid), an ammonium salt (such as ammonium dicarboxylic acid), an organic amine salt (such as triethylamine dicarboxylic acid), a transition metal salt (such as zinc dicarboxylic acid, copper dicarboxylic acid), or a rare earth salt (such as lanthanum dicarboxylic acid). The dicarboxylic acid salt solution / suspension can be prepared by directly dissolving / dispersing the dicarboxylic acid salt with a solvent, or by partially or completely neutralizing the dicarboxylic acid in a solvent with the addition of an alkali or metal oxide (such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium hydroxide, magnesium hydroxide, zinc hydroxide, copper hydroxide, triethylamine, zinc oxide, calcium oxide, etc.). In one embodiment, the present invention demonstrates the preparation of a sodium succinate solution by partially neutralizing succinic acid with sodium hydroxide, followed by the preparation of a succinate-iron(III) complex by mixing the sodium succinate solution with a ferric chloride solution. The resulting product shows no significant difference from the succinate-iron(III) complex prepared with sodium succinate solution. This illustrates that dicarboxylic acids can be in a completely neutralized or partially neutralized form. Since commercially available dicarboxylic acids are typically provided as completely neutralized normal salts, completely neutralized dicarboxylic acid normal salts are preferred. Because the solubility of various dicarboxylic acids varies, using dicarboxylic acids with low water solubility (such as calcium succinate) in excess or with uneven dispersion may result in contamination of the dicarboxylic acid-iron(III) complex product that is difficult to remove. Therefore, water-soluble dicarboxylic acids, such as sodium succinate or ammonium adipate, are preferred.

[0049] According to the above preparation method of dicarboxylic acid-iron(III) complex, the reaction solvent of trivalent iron salt and dicarboxylic acid salt is water or an aqueous organic solvent. Water alone can be used, or a mixture of water and a water-miscible organic solvent (such as methanol, ethanol, acetonitrile, etc.) in a certain proportion can be used. It is necessary to ensure that the iron salt can dissolve. From the perspective of green environmental protection, it is preferred to use only water.

[0050] According to the above method for preparing dicarboxylic acid-iron(III) complexes, the molar ratio of ferric salt to dicarboxylic acid salt is 1:0.5~10. Different molar ratios result in different pH values ​​in the reaction solution, but the molar ratio of iron to dicarboxylic acid in the obtained dicarboxylic acid-iron(III) complexes is consistently around 1:1. From the perspective of saving reactants, the preferred molar ratio of ferric salt to dicarboxylic acid salt is 1:1~2. When the molar ratio of ferric salt to dicarboxylic acid salt is greater than 1:0.5, the reaction yield is low.

[0051] According to the above method for preparing the dicarboxylic acid-iron(III) complex, in step (a), when mixing the dicarboxylic acid salt solution / suspension and the ferric salt solution, the dicarboxylic acid salt solution / suspension can be added to the ferric salt solution, or the ferric salt solution can be added to the dicarboxylic acid salt solution / suspension. In both methods, the molar ratio of iron to dicarboxylic acid in the resulting dicarboxylic acid-iron(III) complex is approximately 1:1. This invention also attempted to directly add the dicarboxylic acid salt in solid form to the ferric salt solution, and directly add the ferric salt in solid form to the dicarboxylic acid salt solution. The molar ratio of iron to dicarboxylic acid in the resulting dicarboxylic acid-iron(III) complex was also approximately 1:1. However, for dicarboxylic acids with poor solubility (such as calcium succinate), direct addition to the ferric salt solution may result in unreacted dicarboxylic acid salt solids being mixed in the obtained dicarboxylic acid-iron(III) complex, leading to a decrease in product purity.

[0052] According to the above preparation method of dicarboxylic acid-iron(III) complex, the pH value of the solution after the trivalent iron salt and dicarboxylic acid salt are mixed and reacted in the solvent is generally in the range of 1.3~7.0, corresponding to a molar ratio of trivalent iron salt and dicarboxylic acid salt of 1:0.5~10. The preparation method of the present invention does not require control of the pH value of the reaction system.

[0053] According to the above preparation method of the dicarboxylic acid-iron(III) complex, the temperature of the stirring in step (b) should be controlled below 60°C to prevent excessive hydrolysis of ferric iron in the solution to produce ferric hydroxide. During the experiment, it was found that at higher reaction temperatures (>80°C), ferric iron hydrolyzes to produce ferric hydroxide, especially after prolonged heating (e.g., more than 2 hours). The precipitate color darkens significantly, the product contains ferric hydroxide, the phosphorus binding capacity decreases, and the phosphorus binding amount per unit mass of iron (mgP / gFe) decreases. In the embodiments given in this invention, some embodiments use 25°C, some use 30°C, some use 40°C, some use 50°C, and some use 60°C. Test results show that the above reaction temperatures do not affect the molar ratio of iron to dicarboxylic acid in the obtained dicarboxylic acid-iron(III) complex (around 1:1), nor do they significantly affect the phosphorus binding amount per unit mass of iron (mgP / gFe) of the obtained dicarboxylic acid-iron(III) complex in aqueous solution. This differs significantly from the preparation process of phosphorus binders based on iron hydroxyl oxide, as high temperatures accelerate the aging and deactivation of iron hydroxyl oxide, reducing its phosphorus-binding capacity—a well-known fact. The preparation of active iron hydroxyl oxide typically involves controlling the reaction temperature at room temperature (10°C–30°C). Although the dicarboxylic acid-iron(III) complex described in this invention can withstand relatively higher reaction temperatures during preparation, from an energy-saving perspective, it is preferable to control the reaction temperature at 20°C–40°C.

[0054] During the experiment, no significant effect of reaction time on the product was found. As shown in the various embodiments of the present invention, from 1 hour to 48 hours, there was no significant difference in the iron content, the molar ratio of iron to dicarboxylic acid, and the phosphorus binding amount per unit mass of iron in the aqueous solution (mgP / gFe) of the obtained dicarboxylic acid-iron(III) complex. It is recommended that the reaction time be controlled between 2 and 8 hours to ensure sufficient reaction.

[0055] In the preparation method provided by this invention, the drying method of the dicarboxylic acid-iron(III) complex is not limited. Common drying methods such as freeze-drying, vacuum drying, atmospheric pressure drying, and spray drying can be used. In some embodiments, freeze-drying was used; in others, vacuum drying at 60°C was used; in still others, drying in an 80°C forced-air oven was used; and in some still others, spray drying was used. The dried product is then pulverized using common methods. Test results show that the dicarboxylic acid-iron(III) complex obtained by any drying method has a considerable phosphorus binding capacity per unit mass of iron (mgP / gFe). This also suggests that the dicarboxylic acid-iron(III) complex prepared by this invention has excellent thermal stability, superior to currently known phosphorus binders based on hydroxyl iron oxide cores. This is because even with ligand protection (such as carbohydrates or humic acid), high temperatures accelerate the aging of hydroxyl iron oxide and reduce its phosphorus binding capacity.

[0056] In one embodiment, adding a neutral inorganic salt, such as sodium chloride, to the reaction solution to increase the ionic strength of the reaction system does not affect the acquisition of the dicarboxylic acid-iron(III) complex of the present invention.

[0057] In one embodiment, the present invention also demonstrates a method of oxidation using a mixture of ferrous sulfate aqueous solution and sodium succinate aqueous solution followed by hydrogen peroxide, which can also yield the dicarboxylic acid-iron(III) complex described in this invention. However, the use of ferrous salt oxidation for preparation is not very operable. The degree of conversion of ferrous iron to ferric iron is greatly affected by various parameters such as pH value, temperature, and oxidant, and ferrous residues are very likely to remain. Ferrous ions have a weak binding capacity with phosphates and are highly irritating to the gastrointestinal tract. In iron-based phosphorus binders, ferrous iron needs to be treated as an impurity. If oxidation is excessive, ferric hydroxide may be generated, reducing phosphorus binding performance. Therefore, the use of ferrous salt oxidation to prepare the dicarboxylic acid-iron(III) complex described in this invention is not recommended.

[0058] It should be emphasized that none of the preparation methods provided in this patent require control of the pH value of the reaction solution, which greatly facilitates scale-up production.

[0059] Furthermore, this invention demonstrates through phosphorus binding capacity tests in aqueous solutions that the phosphorus binding capacity (mgP / gFe) per unit mass of iron of the dicarboxylic acid-iron(III) complex described in this invention is superior to commercially available iron-based phosphorus binders ferric citrate and sucrose hydroxyl oxide. According to publicly available information, the phosphorus binding capacity of ferric citrate and sucrose hydroxyl oxide is significantly affected by pH. Ferric citrate is soluble iron and has good solubility over a wide pH range. The optimal phosphorus binding pH for ferric citrate is 2, and it binds almost no phosphorus in the pH range of 3-8. The optimal phosphorus binding pH for sucrose hydroxyl oxide is also 2, and its phosphorus binding capacity decreases as the pH increases. The dicarboxylic acid-iron(III) complex described in this invention maintains an extremely high phosphorus binding capacity (mgP / gFe) per unit mass of iron consistently within the pH range of 3-7.

[0060] The dicarboxylic acid-iron(III) complex described in this invention is sparingly soluble in water and maintains an extremely high phosphorus binding capacity (mgP / gFe) per unit mass of iron within the pH range of 3-7. Furthermore, the molar ratio of iron to dicarboxylic acid in the dicarboxylic acid-iron(III) complex obtained by various preparation methods provided by this invention is always close to 1:1. It can be inferred that the dicarboxylic acid-iron(III) complex described in this invention is a stable and structurally ordered iron complex, which is significantly different from the structures of known ligand-modified or ligand-protected hydroxyl iron oxide (such as sucrose hydroxyl iron oxide), water-soluble organic iron (such as ferric citrate), and water-soluble carbohydrate iron complexes (such as carboxymaltose iron, isomaltose anhydride iron, and polysaccharide iron complexes).

[0061] Furthermore, this invention further demonstrates through in vivo rat experiments that the dicarboxylic acid-iron(III) complex described in this invention, after oral administration, can bind phosphate in the gastrointestinal tract, reducing phosphate absorption. Moreover, the phosphorus-binding capacity per unit mass of iron in the animal body is significantly higher than that of commercially available sucrose ferric oxide chewable tablets. Using a blank high-phosphorus diet and high-phosphorus diets supplemented with the succinic acid-iron(III) complex, adipic acid-iron(III) complex, fumarate-iron(III) complex prepared in the examples of this invention, and sucrose ferric oxide chewable tablets respectively, rats were fed in metabolic cages for 48 hours, and the total feed intake was recorded. Subsequently, they were fasted and placed in metabolic cages for another 24 hours. All 72-hour urine was collected, and the phosphorus concentration in the urine was measured. The total phosphorus in the 72-hour urine was calculated by multiplying the urine volume. The phosphorus absorption inhibition rate was calculated using the urinary phosphorus (mg / g) normalized to the feed intake as the evaluation index, and the phosphorus absorption inhibition rate (%) normalized to the iron mass was calculated based on the iron content (%) in the added phosphate binder. The results showed that the iron-normalized phosphorus absorption inhibition rates of the succinate-iron(III) complex and the adipic acid-iron(III) complex were comparable (68.4%, 68.0%), superior to the fumarate-iron(III) complex (50.0%), and significantly superior to commercially available sucrose ferric hydroxide chewable tablets (37.6%). Unexpectedly, the fumarate-iron(III) complex exhibited a significantly lower iron-normalized phosphorus absorption inhibition rate in vivo than the succinate-iron(III) and adipic acid-iron(III) complexes, because the fumarate-iron(III) complex had a similar phosphorus binding capacity per unit mass of iron (greater than 500 mg P / g Fe) in in vitro phosphorus binding experiments compared to the succinate-iron(III) and adipic acid-iron(III) complexes. This demonstrates, on the one hand, that the structure of the linear saturated aliphatic dicarboxylic acid-iron(III) complex described in this invention differs from that of the metal-organic framework material fumarate-iron(III) complex. On the other hand, it also illustrates that similar phosphorus binding capacity (mgP / gFe) per unit mass of iron in in vitro aqueous solutions does not equate to similar phosphorus binding capacity per unit mass of iron in vivo. A high phosphorus binding capacity (mgP / gFe) per unit mass of iron in in vitro aqueous solutions does not necessarily imply a strong phosphorus binding capacity per unit mass of iron in animals. Animal experimental results demonstrate the significant clinical advantages of the linear saturated aliphatic dicarboxylic acid-iron(III) complex described in this invention in its development as an oral phosphate binder.

[0062] The linear saturated aliphatic dicarboxylic acid-iron(III) complex described in this invention, upon binding with phosphate in the gastrointestinal tract, releases the dicarboxylic acid and forms the corresponding dicarboxylic acid salt. A portion of this salt will be absorbed by the gastrointestinal tract. Considering that patients with chronic kidney disease and hyperphosphatemia require long-term use of phosphate binders, in addition to monitoring the phosphate-binding capacity of iron-based phosphate binders per unit mass of iron in vivo, the safety of the dicarboxylic acid and its salts also needs to be emphasized. According to publicly available information, short-chain linear saturated aliphatic dicarboxylic acids and their salts have relatively safe oral safety data and are commonly used as flavorings and food acid-base regulators. Therefore, small amounts of these dicarboxylic acids ingested via the gastrointestinal route generally do not pose a safety issue.

[0063] As mentioned in the background section, existing phosphate binders for treating hyperphosphatemia have poor phosphorus binding specificity, low binding capacity, or are prone to causing side effects or have long-term safety issues. In contrast, the dicarboxylic acid-iron(III) complex of this invention exhibits strong phosphorus binding specificity, higher phosphorus binding capacity per unit mass of iron in vivo, higher iron utilization, lower total iron intake, and good safety profile due to the presence of a straight-chain saturated aliphatic dicarboxylic acid in the complex, resulting in a low incidence of adverse reactions. The complex has no noticeable metallic odor, leading to high patient compliance. The straight-chain saturated aliphatic dicarboxylic acid-iron(III) complex of this invention has the potential to be developed into a new generation of phosphate binders for the treatment of hyperphosphatemia.

[0064] The dicarboxylic acid-iron(III) complex of the present invention can be used to prepare oral compositions selected from: (a) solid dosage forms, such as capsules, tablets, granules, dry suspensions, and powders; and (b) suspensions dispersed in a suitable liquid. The compositions can be used in pharmaceuticals, functional foods, and other applications. In the compositions, the dicarboxylic acid-iron(III) complex of the present invention can be used alone, or in combination of two or more dicarboxylic acid-iron(III) complexes, or in combination with other compatible active ingredients, including but not limited to vitamins, amino acids, minerals, and other phosphate binders.

[0065] Conditions that can be treated with the compositions containing the dicarboxylic acid-iron(III) complex of the present invention include high plasma phosphorus levels, hyperphosphatemia caused by renal insufficiency of any degree, acute renal failure, chronic renal failure, and / or end-stage renal disease, including conditions requiring hemodialysis or peritoneal dialysis. The compositions containing the dicarboxylic acid-iron(III) complex of the present invention are particularly suitable for the treatment and / or prevention of hyperphosphatemia in humans and warm-blooded animals, especially companion animals such as dogs and, especially, cats. The dicarboxylic acid-iron(III) complex of the present invention and pharmaceutical compositions containing the dicarboxylic acid-iron(III) complex are even more particularly suitable for patients with hyperphosphatemia, such as those dependent on dialysis, such as hemodialysis and peritoneal dialysis; or patients with advanced chronic kidney disease (CKD), chronic renal failure, chronic renal insufficiency, or end-stage renal disease. Clinical treatment of these conditions using the compositions containing dicarboxylic acid-iron(III) complexes as described in this invention can help alleviate complications associated with these conditions, such as secondary hyperthyroidism, soft tissue calcification, osteodystrophy, hypoparathyroidism, cardiovascular disease or death, renal osteodystrophy, and / or calcification defense.

[0066] The dicarboxylic acid-iron(III) complex of the present invention can be used to prepare functional foods (e.g., fortifiers, supplements, nutritional beverages, health foods, etc.) for the purpose of assisting in the improvement of calcium and phosphorus metabolism abnormalities in patients with chronic kidney disease. In particular, these foods can be used for patients with stage 3-5 kidney disease to reduce intestinal phosphorus absorption, maintain homeostasis of blood phosphorus, blood calcium, and parathyroid hormone (PTH), and assist in improving calcium and phosphorus metabolism disorders.

[0067] Beneficial effects

[0068] The dicarboxylic acid-iron(III) complex of this invention, after oral administration, can bind phosphate from the gastrointestinal tract, reducing phosphate absorption. In in vitro aqueous solutions, the complex of this invention maintains an extremely high phosphate-binding capacity per unit mass of iron (mgP / gFe) within a pH range of 3-7. The complex of this invention maintains a very high phosphate-binding capacity per unit mass of iron in vivo, significantly superior to commercially available sucrose ferric oxide chewable tablets. As an oral phosphate binder, the dicarboxylic acid-iron(III) complex of this invention exhibits strong phosphate binding specificity, stronger phosphate-binding capacity per unit mass of iron in vivo, high iron utilization, low total iron intake, and good safety due to the short-chain, straight-chain, saturated aliphatic dicarboxylic acid contained in the complex, with a low incidence of adverse reactions and high patient compliance. It has the potential to be developed into a new generation of phosphate binders for the treatment of hyperphosphatemia.

[0069] The dicarboxylic acid-iron(III) complex of the present invention has a molar ratio of iron to dicarboxylic acid close to 1:1, stable composition, good thermal stability, and is easy to process and manufacture into pharmaceutical compositions.

[0070] The preparation method of the dicarboxylic acid-iron(III) complex provided by the present invention involves mixing and reacting trivalent iron salt and dicarboxylic acid salt in a solvent. There is no need to control the reaction pH value, the reaction conditions are mild, the preparation method is simple, it has extremely high reaction stability and reproducibility, it is easy to scale up industrially, the raw materials are widely available and inexpensive, the waste treatment is simple, and it is green and environmentally friendly. Attached Figure Description

[0071] Figure 1 The succinic acid-iron(III) complex, adipic acid-iron(III) complex, and sucrose ferric hydroxide chewable tablets (Vivre) prepared for this invention ® (and a picture of the powder after grinding);

[0072] Figure 2 The succinic acid-iron(III) complex, adipic acid-iron(III) complex, and sucrose ferric hydroxide chewable tablets (Vivre) prepared for this invention ® The solution states of the powder after grinding, before and after phosphorus binding, are shown in the diagrams at pH 3 and pH 7. Figure 2 In this invention, A represents the succinic acid-iron(III) complex prepared in this invention. Figure 2 B represents the adipic acid-iron(III) complex prepared in this invention. Figure 2 C in the text refers to commercially available sucrose ferric hydroxide chewable tablets (Vivre). ® );

[0073] Figure 3 For self-made products and commercially available sucrose ferric hydroxide chewable tablets (Vivre) ® ), Lanthanum carbonate chewable tablets (Forslino) ® Comparison of daily medication load. Detailed Implementation

[0074] Example 1

[0075] This embodiment provides the pH values ​​and reaction phenomena after preparing ferric salt solutions using ferric chloride hexahydrate, ferric nitrate nonahydrate, and ferric ammonium sulfate dodecahydrate as iron sources and mixing them with sodium succinate solutions at different molar ratios. A certain amount of ferric chloride hexahydrate, ferric nitrate nonahydrate, or ferric ammonium sulfate dodecahydrate was added to water to prepare an aqueous solution of ferric salts. Sodium succinate was separately added to water to prepare an aqueous solution of sodium succinate. The sodium succinate aqueous solution was added dropwise to the ferric salt aqueous solution at iron:sodium succinate molar ratios of 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:7, and 1:10 at room temperature. After stirring until the pH stabilized, the pH value and precipitation were recorded (see Table 1).

[0076] Table 1. pH values ​​and precipitation after mixing aqueous solutions of different ferric salts with sodium succinate aqueous solution.

[0077]

[0078] +: Indicates that precipitation has occurred; -: Indicates that no obvious precipitation has occurred.

[0079] The above results indicate that when sodium succinate aqueous solution is mixed with ferric salt aqueous solution, precipitation occurs at a relatively low pH value. For ferric chloride aqueous solution and ferric nitrate aqueous solution, precipitation begins with the addition of a small amount of sodium succinate aqueous solution (pH < 1.5). In contrast, the pH value at which ferric trioxide begins to hydrolyze and produce ferric hydroxide is usually above 2. This suggests that the complex formed by sodium succinate and ferric salt is different from ferric hydroxide.

[0080] Centrifuging the above solutions, the supernatant of the solutions with an iron:sodium succinate molar ratio of 1:0.5 and 1:1 was yellow, indicating the presence of unreacted iron since the pH < 2.5; while the supernatant of the reaction solutions with iron:sodium succinate molar ratios of 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:7, and 1:10 was colorless after centrifugation, and the precipitate weights were similar, indicating that adding excess sodium succinate can make the iron reaction complete, and the yield of the succinate-iron(III) complex is only related to the amount of iron.

[0081] Example 2

[0082] Ferric chloride aqueous solution was prepared using ferric chloride hexahydrate as the iron source, and sodium succinate aqueous solution was prepared using sodium succinate. The sodium succinate aqueous solution was added to the ferric chloride aqueous solution according to the iron:sodium succinate molar ratio of 1:0.5, 1:1, 1:1.5, 1:2, 1:3, and 1:10 to prepare succinate-iron(III) complex. Prepare a ferric chloride aqueous solution by dissolving 8.1 g of ferric chloride hexahydrate (30 mmol) in 100 mL of water, and make 6 parallel aliquots. Separately, prepare sodium succinate aqueous solutions by dissolving 2.43 g (15 mmol), 4.86 g (30 mmol), 7.29 g (45 mmol), 9.72 g (60 mmol), and 14.58 g (90 mmol) of sodium succinate in 100 mL of water and 48.6 g (300 mmol) in 500 mL of water, respectively. Use a peristaltic pump to slowly add the sodium succinate solution to the ferric chloride aqueous solution, keep at 30 °C and stir for 2 hours, centrifuge, wash the precipitate with water until no chloride ions are detected, freeze-dry the precipitate, and label the 6 products as S2-1, S2-2, S2-3, S2-4, S2-5, and S2-6, respectively.

[0083] Example 3

[0084] Ferric nitrate aqueous solution was prepared using ferric nitrate nonahydrate as the iron source, and sodium succinate aqueous solution was prepared using sodium succinate. The sodium succinate aqueous solution was added to the ferric nitrate aqueous solution at a molar ratio of 1:1.5 to prepare the succinate-iron(III) complex. 16.62 g of ferric nitrate nonahydrate (41 mmol) was dissolved in 200 mL of water to prepare the ferric nitrate aqueous solution, and 10 g of sodium succinate (62 mmol) was dissolved in 100 mL of water to prepare the sodium succinate aqueous solution. The sodium succinate aqueous solution was slowly added dropwise to the ferric nitrate aqueous solution using a peristaltic pump. The mixture was kept at 30 °C with stirring for 2 hours, centrifuged, and the precipitate was washed with water until no nitrate ions were detected. The precipitate was then dried in an oven at 80 °C. The product was labeled S3.

[0085] Example 4

[0086] Ferric ammonium sulfate dodecahydrate was used as the iron source to prepare an aqueous solution of ferric ammonium sulfate, and sodium succinate was used to prepare an aqueous solution of sodium succinate. The sodium succinate aqueous solution was added to the ferric ammonium sulfate aqueous solution at a molar ratio of 1:1.5 to prepare the succinate-iron(III) complex. 19.8 g of ferric ammonium sulfate dodecahydrate (41 mmol) was dissolved in 200 mL of water to prepare the ferric ammonium sulfate aqueous solution, and 10 g of sodium succinate (62 mmol) was dissolved in 100 mL of water to prepare the sodium succinate aqueous solution. The sodium succinate aqueous solution was slowly added dropwise to the ferric ammonium sulfate aqueous solution using a peristaltic pump. The mixture was kept at 30 °C with stirring for 2 hours, centrifuged, and the precipitate was washed with water until no nitrate ions were detected. The precipitate was then dried in an 80 °C oven. The product was labeled S4.

[0087] Example 5

[0088] Ferric chloride hexahydrate was used as the iron source to prepare an aqueous solution of ferric chloride, and sodium succinate was used to prepare an aqueous solution of sodium succinate. The ferric chloride aqueous solution was added to the sodium succinate aqueous solution at a molar ratio of 1:1.5 to prepare the succinate-iron(III) complex. 22.2 g of ferric chloride hexahydrate (82 mmol) was dissolved in 200 mL of water to prepare the ferric chloride aqueous solution, and 20 g of sodium succinate (123 mmol) was dissolved in 200 mL of water to prepare the sodium succinate aqueous solution. The ferric chloride aqueous solution was slowly added dropwise to the sodium succinate aqueous solution using a peristaltic pump. The mixture was kept at 50 °C and stirred for 4 hours. After centrifugation, the precipitate was washed with water until no chloride ions were detected. The precipitate was dispersed in water to form a suspension, and spray-dried to obtain a dry solid. The product was labeled S5.

[0089] Example 6

[0090] Ferric chloride hexahydrate was used as the iron source to prepare an aqueous solution of ferric chloride, and sodium succinate was used to prepare an aqueous solution of sodium succinate. Sodium chloride was added to the sodium succinate aqueous solution to increase the ionic strength. The ferric chloride aqueous solution was added to the sodium succinate aqueous solution containing sodium chloride at a molar ratio of 1:1.5 to prepare the succinate-iron(III) complex. 22.2 g of ferric chloride hexahydrate (82 mmol) was dissolved in 200 mL of water to prepare an aqueous solution of ferric chloride. 20 g of sodium succinate (123 mmol) and 4.77 g of sodium chloride (82 mmol) were dissolved in 200 mL of water to prepare an aqueous solution of sodium succinate containing sodium chloride. The ferric chloride solution was slowly added dropwise to the sodium succinate aqueous solution containing sodium chloride using a peristaltic pump. The mixture was kept at 50 °C and stirred for 2 hours. After centrifugation, the precipitate was washed with water until no chloride ions were detected. The precipitate was freeze-dried, and the product was labeled S6.

[0091] Example 7

[0092] Ferric chloride aqueous solution was prepared using ferric chloride hexahydrate as the iron source. Sodium succinate aqueous solution was prepared by neutralization of succinic acid with sodium hydroxide. The ferric chloride aqueous solution was added to the sodium succinate aqueous solution at a 1:1 molar ratio of iron to sodium succinate to prepare the succinate-iron(III) complex. 57.2 g of ferric chloride hexahydrate (212 mmol) was dissolved in 200 mL of water to prepare a ferric chloride solution. Separately, 25 g of succinic acid (212 mmol) was dispersed in 200 mL of water, and 16.99 g of sodium hydroxide (424 mmol) was added and stirred until dissolved to prepare a sodium succinate aqueous solution. The ferric chloride aqueous solution was slowly added dropwise to the sodium succinate aqueous solution using a peristaltic pump. The mixture was kept at 30 °C with stirring for 6 hours, centrifuged, and the precipitate was washed with water until no chloride ions were detected. The precipitate was dried under reduced pressure at 60 °C, and the product was labeled S7.

[0093] Example 8

[0094] Ferric chloride aqueous solution was prepared using ferric chloride hexahydrate as the iron source, and ammonium succinate aqueous solution was prepared using ammonium succinate. The ferric chloride aqueous solution was added to the ammonium succinate aqueous solution at a molar ratio of 1:1.5 to prepare the succinate-iron(III) complex. 35.5 g of ferric chloride hexahydrate (131 mmol) was dissolved in 250 mL of water to prepare the ferric chloride aqueous solution, and 30 g of ammonium succinate (197 mmol) was dissolved in 250 mL of water to prepare the ammonium succinate aqueous solution. The ferric chloride aqueous solution was slowly added dropwise to the ammonium succinate aqueous solution using a peristaltic pump. The mixture was kept at 50 °C with stirring for 1 hour, centrifuged, and the precipitate was washed with water until no chloride ions were detected. The precipitate was then freeze-dried, and the product was labeled S8.

[0095] Example 9

[0096] Ferric chloride aqueous solution was prepared using ferric chloride hexahydrate as the iron source. Sodium succinate aqueous solution was prepared by adding succinic acid and sodium acetate (molar ratio 1:2). The succinate-iron(III) complex was prepared by adding the ferric chloride aqueous solution to the sodium succinate aqueous solution at a molar ratio of 1:1. 20 g of ferric chloride hexahydrate (74 mmol) was dissolved in 100 mL of water to prepare a ferric chloride aqueous solution. Separately, 8.74 g of succinic acid (74 mmol) was dispersed in 300 mL of water, and 12.15 g of sodium acetate (148 mmol) was added to prepare a sodium succinate aqueous solution. The ferric chloride aqueous solution was slowly added dropwise to the sodium succinate aqueous solution using a peristaltic pump. The mixture was kept at 30 °C with stirring for 2 hours, centrifuged, and the precipitate was washed with water until no chloride ions were detected. The precipitate was then freeze-dried, and the product was labeled S9.

[0097] Example 10

[0098] Ferric chloride hexahydrate was used as the iron source to prepare an ethanolic solution of ferric chloride, and sodium succinate was used to prepare an aqueous solution of sodium succinate. The sodium succinate aqueous solution was added to the ferric chloride ethanolic solution at a molar ratio of 1:1.5 to prepare the succinate-iron(III) complex. 5.55 g of ferric chloride hexahydrate (20.5 mmol) was dissolved in 25 mL of ethanol to prepare the ferric chloride ethanolic solution. Separately, 5 g of sodium succinate (30.8 mmol) was dissolved in 25 mL of water to prepare the sodium succinate aqueous solution. The sodium succinate solution was slowly added dropwise to the ferric chloride ethanolic solution using a peristaltic pump. The mixture was kept at 25 °C with stirring for 24 hours, centrifuged, and the precipitate was washed with water until no chloride ions were detected. The precipitate was then dried under reduced pressure at 60 °C, and the product was labeled S10.

[0099] Example 11

[0100] Ferric chloride aqueous solution was prepared using ferric chloride as the iron source. Sodium dicarboxylate aqueous solution was prepared by neutralizing glutaric acid, adipic acid, pimelic acid, and octanoic acid with sodium hydroxide. The sodium dicarboxylate aqueous solution was slowly added dropwise to the ferric chloride aqueous solution using a peristaltic pump at a molar ratio of 1:2. The mixture was kept at 50°C and stirred for 2 hours. The precipitate was washed with water until no chloride ions were detected. The precipitate was dried under reduced pressure at 60°C to prepare dicarboxylate-iron(III) complexes. The products were labeled as S11-1, S11-2, S11-3, and S11-4.

[0101] Example 12

[0102] Preparation of succinic acid-adipic acid-iron(III) complex. Ferric chloride aqueous solution was prepared using ferric chloride as the iron source. Sodium succinate and ammonium adipate were added to the ferric chloride aqueous solution at different molar ratios to prepare aqueous solutions containing sodium succinate and ammonium adipate. The succinic acid-adipic acid-iron(III) complex was prepared by adding the aqueous solution containing sodium succinate and ammonium adipate to the ferric chloride aqueous solution at a molar ratio of 1:2. 10 g of ferric chloride hexahydrate (37 mmol) was dissolved in 100 mL of water to prepare a ferric chloride aqueous solution, and three portions were prepared. Separately, 6 g sodium succinate (37 mmol) + 6.66 g ammonium adipate (37 mmol), 3 g sodium succinate (18.5 mmol) + 10 g ammonium adipate (55.5 mmol), and 9 g sodium succinate (55.5 mmol) + 3.33 g ammonium adipate (18.5 mmol) were dissolved in 100 mL of water to prepare aqueous solutions containing sodium succinate and ammonium adipate (molar ratios 1:1, 1:3, and 3:1). Using a peristaltic pump, the aqueous solutions containing sodium succinate and ammonium adipate were slowly added dropwise to an aqueous solution of ferric chloride. The mixture was kept at 40 °C with stirring for 4 hours. The precipitate was washed with water until no chloride ions were detected. The precipitate was then dried under reduced pressure at 60 °C to prepare succinic acid-adipic acid-ferric (III) complexes, labeled S12-1, S12-2, and S12-3.

[0103] Example 13

[0104] Ferric chloride hexahydrate was used as the iron source to prepare an aqueous solution of ferric chloride. Sodium succinate was prepared by adding sodium hydroxide to succinic acid. The sodium succinate solution was added to the ferric chloride solution at a molar ratio of 1:5 to prepare the succinate-iron(III) complex. 10 g of ferric chloride hexahydrate (37 mmol) was dissolved in 100 mL of water to prepare an aqueous solution of ferric chloride. Separately, 21.85 g of succinic acid (185 mmol) was dispersed in 200 mL of water, and 7.4 g of sodium hydroxide (185 mmol) was added and stirred until dissolved to prepare an aqueous solution of sodium succinate. The sodium succinate solution was slowly added dropwise to the ferric chloride solution using a peristaltic pump. The mixture was kept at 30 °C and stirred for 12 hours. The precipitate was washed with water until no chloride ions were detected. The precipitate was then dried under reduced pressure at 60 °C to prepare the succinate-iron(III) complex, labeled as S13.

[0105] Example 14

[0106] Ferric chloride hexahydrate was used as the iron source to prepare an aqueous solution of ferric chloride. Calcium succinate was dispersed in water to prepare a calcium succinate suspension. The ferric chloride aqueous solution was added to the calcium succinate suspension at a molar ratio of 1:1.5 to prepare the succinate-iron(III) complex. 10 g of ferric chloride hexahydrate (37 mmol) was dissolved in 100 mL of water to prepare an aqueous solution of ferric chloride. Separately, 9.67 g of solid calcium succinate (55.5 mmol) was dispersed in 100 mL of water to prepare a calcium succinate suspension. The ferric chloride aqueous solution was slowly added dropwise to the calcium succinate suspension using a peristaltic pump. The mixture was stirred at 25 °C for 48 hours. The precipitate was washed with water until no chloride ions were detected. The precipitate was then freeze-dried to prepare the succinate-iron(III) complex, labeled as S14.

[0107] Example 15

[0108] Ferric chloride hexahydrate was used as the iron source to prepare an aqueous solution of ferric chloride. Magnesium succinate was prepared by adding magnesium hydroxide to succinic acid. The ferric chloride aqueous solution was added to the magnesium succinate aqueous solution at a molar ratio of 1:1.5 to prepare the succinate-iron(III) complex. 15.25 g of ferric chloride hexahydrate (56.5 mmol) was dissolved in 100 mL of water to prepare the ferric chloride aqueous solution. Separately, 10 g of succinic acid (84.7 mmol) was dispersed in 100 mL of water, and 4.94 g of magnesium hydroxide (84.7 mmol) was added and stirred thoroughly to prepare the magnesium succinate aqueous solution. The ferric chloride aqueous solution was slowly added dropwise to the magnesium succinate aqueous solution using a peristaltic pump. The mixture was kept at 40 °C and stirred for 2 hours. The precipitate was washed with water until no chloride ions were detected. The precipitate was then dried under reduced pressure at 60 °C to prepare the succinate-iron(III) complex, and the product was labeled S15.

[0109] Example 16

[0110] Ferric chloride hexahydrate was used as the iron source to prepare an aqueous solution of ferric chloride. Zinc succinate suspension was prepared by adding zinc oxide to succinic acid. The ferric chloride aqueous solution was added to the zinc succinate suspension at a molar ratio of 1:1.5 to prepare the succinate-iron(III) complex. 15.25 g of ferric chloride hexahydrate (56.5 mmol) was dissolved in 100 mL of water to prepare an aqueous solution of ferric chloride. Separately, 10 g of succinic acid (84.7 mmol) was dispersed in 100 mL of water, and 6.9 g of zinc oxide (84.7 mmol) was added and stirred thoroughly to prepare a zinc succinate suspension. The ferric chloride aqueous solution was slowly added dropwise to the zinc succinate suspension using a peristaltic pump. The mixture was kept at 40 °C and stirred for 2 hours. The precipitate was washed with water until no chloride ions were detected. The precipitate was then dried under reduced pressure at 60 °C to prepare the succinate-iron(III) complex, labeled as S16.

[0111] Example 17

[0112] Ferric chloride hexahydrate was used as the iron source to prepare an aqueous solution of ferric chloride. Succinic acid and copper hydroxide were added to prepare a copper succinate suspension. The ferric chloride aqueous solution was added to the copper succinate suspension at a molar ratio of 1:1 to prepare the succinate-iron(III) complex. 20 g of ferric chloride hexahydrate (74 mmol) was dissolved in 100 mL of water to prepare an aqueous solution of ferric chloride. Separately, 8.74 g of succinic acid (74 mmol) was dispersed in 100 mL of water, and 7.23 g of copper hydroxide (74 mmol) was added and stirred thoroughly to prepare a copper succinate suspension. The ferric chloride aqueous solution was slowly added dropwise to the zinc succinate suspension using a peristaltic pump. The mixture was kept at 40 °C and stirred for 4 hours. The precipitate was washed with water until no chloride ions were detected. The precipitate was then freeze-dried to prepare the succinate-iron(III) complex, and the product was labeled S17.

[0113] Example 18

[0114] Calcium succinate was added to a lanthanum chloride solution to prepare lanthanum succinate, which was then dried. The dried lanthanum succinate solid was added to a ferric chloride aqueous solution at a molar ratio of 1:0.2 to prepare a succinate-iron(III) complex. 40 g of lanthanum chloride heptahydrate was dissolved in 400 mL of water to prepare a lanthanum chloride solution. 18.7 g of calcium succinate solid was added to the lanthanum chloride solution, stirred overnight at room temperature, and the precipitate was washed with water and freeze-dried to obtain lanthanum succinate (the solid contained approximately 45% succinic acid). 10 g of ferric chloride hexahydrate (37 mmol) was dissolved in 100 mL of water to prepare a ferric chloride aqueous solution. 2 g of lanthanum succinate (approximately 7.3 mmol) was added to the ferric chloride aqueous solution, stirred at 25 °C for 18 hours, and the precipitate was washed with water until no chloride ions were detected. The precipitate was freeze-dried to prepare a succinate-iron(III) complex, labeled S18.

[0115] Example 19

[0116] Ferrous sulfate heptahydrate was used as the iron source to prepare an aqueous solution of ferrous sulfate. Sodium succinate was added to water to prepare an aqueous solution of sodium succinate. The sodium succinate aqueous solution was added to the ferrous sulfate aqueous solution at a molar ratio of 1:1.5, followed by oxidation with hydrogen peroxide to prepare the succinate-iron(III) complex. 17.16 g of ferrous sulfate heptahydrate (61.7 mmol) was dissolved in 100 mL of water to prepare an aqueous solution of ferrous sulfate. 15 g of sodium succinate (92.6 mmol) was dissolved in 150 mL of water to prepare an aqueous solution of sodium succinate. The sodium succinate aqueous solution was slowly added dropwise to the ferrous sulfate aqueous solution using a peristaltic pump. After the addition was complete, the pH of the solution was approximately 6.8, and it was a slightly turbid, yellowish-green solution. Then, 5 mL of hydrogen peroxide was added, and the solution was kept at 40 °C and stirred for 2 hours, producing a large amount of brown precipitate. The precipitate was washed with water until no chloride ions were detected. The precipitate was dried under reduced pressure at 60 °C to prepare the succinate-iron(III) complex, and the product was labeled as S19.

[0117] Example 20

[0118] The succinate-iron(III) complex was prepared by directly adding solid ferric chloride to an aqueous solution of sodium succinate at a molar ratio of 1:1.2. 7.19 g of sodium succinate (44 mmol) was dissolved in 100 mL of water, and 10 g of solid ferric chloride hexahydrate (37 mmol) was added directly to the aqueous solution of sodium succinate. The mixture was stirred at 25 °C for 2 hours, and the precipitate was washed with water until no chloride ions were detected. The precipitate was then freeze-dried, and the product was labeled S20.

[0119] Comparative Example 1

[0120] Ferric chloride aqueous solution was prepared using ferric chloride as the iron source. Sodium dicarboxylate aqueous solution was prepared by neutralizing azelaic acid and sebacic acid with sodium hydroxide. The sodium dicarboxylate aqueous solution was slowly added dropwise to the ferric chloride aqueous solution using a peristaltic pump at a molar ratio of 1:2. The mixture was kept at 50°C and stirred for 2 hours. The precipitate was washed with water until no chloride ions were detected. The precipitate was dried under reduced pressure at 60°C to prepare azelaic acid-iron(III) complex and sebacic acid-iron(III) complex. The products were labeled as D1-1 and D1-2.

[0121] Comparative Example 2

[0122] Ferric chloride hexahydrate was used as the iron source to prepare an aqueous solution of ferric chloride. Sodium fumarate was prepared by adding fumaric acid and sodium hydroxide. The fumarate-iron(III) complex was prepared by adding the sodium fumarate aqueous solution to the ferric chloride aqueous solution at a molar ratio of 1:2. 50 g of ferric chloride hexahydrate (185 mmol) was dissolved in 250 mL of water to prepare an aqueous solution of ferric chloride. Separately, 43 g of fumaric acid (370 mmol) was dispersed in 250 mL of water, and 29.6 g of sodium hydroxide (740 mmol) was added and stirred to prepare an aqueous solution of sodium fumarate. The sodium fumarate solution was slowly added dropwise to the ferric chloride aqueous solution using a peristaltic pump. The mixture was kept at 50 °C and stirred for 4 hours. The precipitate was washed with water until no chloride ions were detected. The precipitate was then freeze-dried to prepare the fumarate-iron(III) complex, and the product was labeled D2.

[0123] Comparative Example 3

[0124] First, active ferric hydroxide was prepared. Then, succinic acid and ferric hydroxide were mixed and reacted in water. After washing, succinic acid-modified ferric hydroxide was obtained. 10 g of ferric chloride hexahydrate (37 mmol) was dissolved in 100 mL of water, and the pH was adjusted to about 7.0 with sodium hydroxide solution. The mixture was stirred at room temperature for 1 hour. The precipitate was then washed with water until no chloride ion residue remained. The washed precipitate was dispersed in 100 mL of water, and two parallel preparations were made. 4.37 g of succinic acid (37 mmol) and 8.73 g of succinic acid (74 mmol) were added to the ferric hydroxide suspension according to the iron:succinic acid molar ratio of 1:1 and 1:2, respectively. The mixture was stirred at 25 °C for 2 hours. After centrifugation, the precipitate was washed with water and freeze-dried to prepare succinic acid-modified ferric hydroxide. The products were labeled D3-1 and D3-2.

[0125] Comparative Example 4

[0126] Succinic acid and ferric chloride were first dissolved in water, and then the pH was raised to above 4 with sodium hydroxide to obtain succinic acid-modified ferric hydroxide. 10 g of ferric chloride hexahydrate (37 mmol) and 4.37 g of succinic acid (37 mmol) were added to 200 mL of water and thoroughly mixed. Two parallel batches were prepared, and the pH was raised to 4.0 and 5.0 respectively with sodium hydroxide solution. The mixtures were then incubated at 25 °C with stirring for 2 hours. The precipitates were washed until no chloride ions were detected, centrifuged, and the precipitates were freeze-dried to prepare succinic acid-modified ferric hydroxide. The products were labeled D4-1 and D4-2.

[0127] Example 21

[0128] This embodiment uses conventional instrumental analysis methods to test the iron and dicarboxylic acid content in the products of Examples 2-20 and Comparative Examples 1-4. The products were dissolved in concentrated hydrochloric acid by heating to form a clear yellow solution. An appropriate amount of the acid-degraded solution was taken and the iron content was determined by the o-phenanthroline colorimetric method. Another appropriate amount of the acid-degraded solution was added to disodium hydrogen phosphate solution to neutralize to pH 2-3, causing iron to precipitate. The supernatant was then taken and the dicarboxylic acid content was determined by high performance liquid chromatography. The iron and dicarboxylic acid contents are calculated based on dried products after deducting moisture. The results are shown in Table 2.

[0129] Table 2. Iron and dicarboxylic acid content and molar ratio in the products obtained from Examples 2-20 and Comparative Examples 1-4

[0130]

[0131]

[0132]

[0133] As shown in the table above, the samples prepared in Examples 2-20 using different iron salts, different dicarboxylic acids, different molar ratios of ferric salts to dicarboxylic acids, and different preparation methods all had iron contents between 20% and 30%. The molar ratio of iron to dicarboxylic acids in the products ranged from 1:0.8 to 1.2, with a greater concentration between 1:0.9 and 1.1. Furthermore, the iron content was related to the molecular weight of the dicarboxylic acid; the longer the carbon chain, the lower the iron content. Particularly unexpectedly, in Example 12, the products prepared by reacting two dicarboxylic acids (sodium succinate and ammonium adipate) with ferric chloride solution at three different molar ratios (1:1, 1:3, and 3:1) still had a molar ratio of iron to total dicarboxylic acids close to 1:1. Moreover, the molar ratio of the two dicarboxylic acids in the product was close to the molar ratio of the two dicarboxylic acids in the feed, indicating that the reaction between the mixed dicarboxylic acid and the ferric salt in the solvent occurred simultaneously. The various dicarboxylic acid-iron(III) complexes prepared by the preparation method described in this invention have stable compositions, similar structures, and high reproducibility.

[0134] In Comparative Example 1, although the iron content of the azelaic acid-iron(III) complex and the sebacic acid-iron(III) complex prepared by the method described above is less than 20%, the molar ratio of iron to dicarboxylic acid is close to 1:1. It can be reasonably inferred that the reaction products of linear saturated aliphatic dicarboxylic acids with trivalent iron salts with longer carbon chains all have the characteristic of a molar ratio of iron to dicarboxylic acid close to 1:1. However, the longer the carbon chain, the lower the iron content per unit weight of the complex. In Comparative Example 2, the iron content of the fumaric acid-iron(III) complex prepared by the method described above using sodium fumarate is 25.31%, and the molar ratio of iron to fumaric acid is 1:1.15, which is also within the range of 1:0.8 to 1.2 of the iron to dicarboxylic acid molar ratio. The iron content per unit mass of the fumaric acid-iron(III) complex and the succinic acid-iron(III) complex are similar. In Comparative Example 3, the iron content of the two succinic acid-modified iron hydroxyoxide products prepared by mixing succinic acid with freshly prepared iron hydroxyoxide in solution at molar ratios of 1:1 and 1:2 was greater than 40%, and the molar ratio of iron to succinic acid was 1:0.30 and 1:0.42, which was significantly lower than the range of 1:0.8~1.2. This indicates that succinic acid may not be able to fully modify the iron in the already formed iron hydroxyoxide, and also suggests that the dicarboxylic acid-iron(III) complex described in this invention cannot be obtained by this preparation method. In Comparative Example 4, ferric salts and succinic acid were thoroughly mixed in an aqueous solution, and then the pH was adjusted to 4.0 and 5.0 with sodium hydroxide. The iron content of the two succinic acid-modified iron hydroxyoxide products prepared was greater than 30%, and the molar ratio of iron to succinic acid was 1:0.78 and 1:0.70, respectively. The sample obtained by adjusting the pH to 5.0 had a higher iron content and less succinic acid than the sample obtained by adjusting the pH to 4.0. This proves that the product composition obtained by the common preparation method of dicarboxylic acid-modified iron hydroxyoxide by mixing dicarboxylic acid with iron and increasing the pH value is related to the reaction pH value. The molar ratio of iron to dicarboxylic acid in the dicarboxylic acid-modified iron hydroxyoxide products obtained under different pH conditions varies.

[0135] Example 22

[0136] This embodiment tests the phosphorus binding capacity of the products in Examples 2-20, Comparative Examples 1-4, and commercially available sucrose ferric hydroxide chewable tablets in aqueous phosphate buffer.

[0137] Preparation of phosphate buffer solution (containing 80 mmol / L sodium chloride, 100 mmol / L BES, and 1.5 g / L phosphorus): Take 9.35 g sodium chloride, 42.65 g N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) and 36.8 g sodium phosphate dodecahydrate, add 2 L of water and stir until dissolved. Adjust the pH to 3.0 and 7.0 with hydrochloric acid.

[0138] Test method: Take 0.2g of each product after grinding or sucrose ferric hydroxide chewable tablets, place them in 50mL of the above phosphate buffer solution, stir in a 37℃ water bath for 2 hours, centrifuge and take the supernatant to test the phosphorus concentration. Calculate the phosphorus binding capacity of each product by the difference in the decrease of phosphorus concentration in the supernatant, expressed as mgP / g product or mgP / g Fe.

[0139] In this embodiment, a commercially available phosphorus test kit based on the phosphomolybdic acid colorimetric method (item number: C006-1-1, Nanjing Jiancheng Bioengineering Institute) was used to test the phosphorus content. The test results are shown in Table 3 below.

[0140] Table 3 Comparison of phosphorus binding amounts of the products from Examples 2-20 and Comparative Examples 1-4, and sucrose ferric hydroxide chewable tablets in aqueous phosphate buffer solutions at pH 3 and pH 7.

[0141]

[0142]

[0143]

[0144] As shown in the table above, the phosphorus binding capacity of the sucrose ferric hydroxide chewable tablets is consistent with publicly reported information. The phosphorus binding capacity of iron per unit mass is affected by pH; at pH 3, the phosphorus binding capacity of iron per unit mass (227.85 mg P / g Fe) is higher than that at pH 7 (182.90 mg P / g Fe). Furthermore, the dicarboxylic acid-iron(III) complexes prepared under various conditions in Examples 2-20 all exhibit very high phosphorus binding capacities of iron per unit mass at both pH 3 and pH 7 (almost all exceeding 500 mg P / g Fe). The phosphorus binding capacity of iron per unit mass of the dicarboxylic acid-iron(III) complex described in this invention is significantly superior to that of commercially available sucrose ferric hydroxide in aqueous solution.

[0145] Figure 1 The succinate-iron(III) complex prepared in Example 5, the adipic acid-iron(III) complex prepared in Example 11, and commercially available sucrose ferric hydroxide chewable tablets (Vivre) are demonstrated. ® The images show the actual product of the succinate-iron(III) complex and the adipic acid-iron(III) complex, and it can be seen that their colors are lighter than those of commercially available sucrose ferric hydroxide chewable tablets (Vivre). ® ). Figure 2 The following were demonstrated: succinate-iron(III) complex, adipic acid-iron(III) complex, and sucrose ferric hydroxide chewable tablets (Vivre). ®The powder was dispersed in phosphate aqueous solutions at pH 3 and pH 7. The solution states before and after phosphate binding were directly observed. The precipitate color of the succinic acid-iron(III) complex and the adipic acid-iron(III) complex changed from light reddish-brown to off-white (in pH 3 solution) or light yellow (in pH 7 solution) in aqueous solution before and after phosphate binding. This indicates that the succinic acid-iron(III) complex and the adipic acid-iron(III) complex prepared in this invention have a high iron-phosphate binding rate. Meanwhile, the sucrose ferric hydroxide chewable tablets (Vivre) ® The precipitate formed after the powder binds to phosphate in aqueous solution still shows a distinct brownish-red color, indicating that the binding rate of iron to phosphate is low.

[0146] The azelaic acid-iron(III) complex and sebacic acid-iron(III) complex prepared in Comparative Example 1 are straight-chain saturated aliphatic dicarboxylic acid-iron(III) complexes obtained by the preparation method described in this invention. Their phosphorus binding amount per unit mass of iron in aqueous solution is comparable to that of the dicarboxylic acid-iron(III) complex with a shorter carbon chain (approximately 500 mg P / g Fe). However, due to the longer carbon chain length, the iron content per unit mass of the complex is less than 20%, and the total phosphorus binding amount per unit mass of the complex is less than 100 mg P / g of the complex. The amount of complex required to bind the same mass of phosphate is greater than that of the dicarboxylic acid-iron(III) complex with a shorter carbon chain. Therefore, it is not suitable for development as a pharmaceutical oral phosphate binder. The iron content of the fumarate-iron(III) complex prepared in Comparative Example 2 is similar to that of the succinate-iron(III) complex in the examples (around 25%), the molar ratio of iron to fumarate is 1:1.15, and the composition ratio is similar to that of the succinate-iron(III) complex. The phosphorus binding capacity per unit mass of iron in aqueous solution is also comparable (>500 mg P / g Fe). Based on this result, it cannot be confirmed that the succinate-iron(III) complex has a higher phosphorus binding capacity per unit mass of iron than the fumarate-iron(III) complex in animals. Further comparison through in vivo animal experiments is needed. In Comparative Example 3, the two succinic acid-modified ferric hydroxide products prepared by reacting succinic acid with freshly prepared ferric hydroxide in solution at molar ratios of 1:1 and 2:1 both had iron contents greater than 40%, with iron to succinic acid molar ratios of 1:0.30 and 1:0.42. The phosphorus binding capacity per unit mass of iron in aqueous solution was approximately 200-300 mg P / g Fe. This is comparable to that of sucrose ferric hydroxide chewable tablets (Vivre). ®The results are comparable, indicating that the succinic acid-modified ferric hydroxide prepared by reacting active ferric hydroxide with succinic acid in aqueous solution using the same method as sucrose ferric hydroxide has a similar phosphorus binding capacity per unit mass of iron as sucrose ferric hydroxide. A significant portion of the iron remains unbound to phosphate. In Comparative Example 4, the two succinic acid-modified ferric hydroxide products prepared by thoroughly mixing ferric salt with succinic acid in aqueous solution and adjusting the pH to 4.0 and 5.0 with sodium hydroxide have iron contents greater than 30%, with iron to succinic acid molar ratios of 1:0.78 and 1:0.70, respectively. Their phosphorus binding capacity per unit mass of iron (approximately 400 mg P / g Fe) is higher than that of sucrose ferric hydroxide chewable tablets (Vivre). ® The results of comparing the succinic acid-modified iron(III) hydroxyacid prepared in Comparative Example 3 with those in Comparative Example 4 (approximately 200-300 mg P / g Fe) demonstrate that the degree of modification of iron(III) hydroxyacid hydroxyacid obtained by mixing succinic acid with ferric salts beforehand and then raising the pH value is higher. However, pH value significantly affects the molar ratio of iron to succinic acid in the product. The molar ratio of iron to dicarboxylic acid in the dicarboxylic acid-modified iron(III) hydroxyacid products obtained under different pH conditions varies, and the phosphorus binding amount per unit mass of iron in the corresponding products also varies. In aqueous solution, the phosphorus binding amount per unit mass of iron (mg P / g Fe) of the iron(III) hydroxyacid hydroxyacid prepared in Comparative Examples 3 and 4 is significantly lower than that of the succinic acid-iron(III) complex prepared in the various embodiments of the present invention, further demonstrating the difference in fine structure between the dicarboxylic acid-iron(III) complex and the dicarboxylic acid-modified iron(III) hydroxyacid hydroxyacid described in the present invention.

[0147] Example 23

[0148] This embodiment demonstrates through in vivo animal experiments that the dicarboxylic acid-iron(III) complex described in this invention can bind phosphate in the gastrointestinal tract, reducing phosphate absorption, and that the iron-phosphate binding capacity per unit mass in animals is significantly higher than that of commercially available sucrose ferric hydroxide chewable tablets (Vivre). ® ).

[0149] Dietary intake is a crucial source of phosphorus in animals. In healthy rats, phosphorus ingested through food is primarily absorbed by the intestines and excreted by the kidneys. A high-phosphorus diet is prepared by adding inorganic phosphates to the maintenance diet of normal rats. After consuming a high-phosphorus diet, healthy rats absorb more phosphorus into their bloodstream, and excess phosphorus is excreted in the urine. Adding phosphate binders to the high-phosphorus diet causes the binders to bind with phosphorus in the gastrointestinal tract, precipitating the phosphorus and reducing its absorption, resulting in decreased urinary phosphorus excretion. Therefore, by measuring the amount of phosphorus excreted in the urine of rats fed high-phosphorus diets with different phosphate binders, the phosphorus-binding capacity of phosphate binders in the animal's gastrointestinal tract can be compared. Conducting experiments in metabolic cages allows for the separation of urine and feces, facilitating urine collection and eliminating fecal interference.

[0150] Blank feed: Take 12.5g of corn starch and mix it evenly with 487.5g of powdered feed (450g of crushed normal rat maintenance feed (compliant with GB13078 and GB14924.2, containing 6-12g of total phosphorus and 10-18g of calcium per kilogram) and 37.5g of corn starch.

[0151] Blank high-phosphorus diet: Take 12.5g of corn starch and 487.5g of powdered high-phosphorus diet (450g of crushed normal rat maintenance diet, plus 8.24g of anhydrous potassium dihydrogen phosphate, 4.26g of anhydrous dipotassium hydrogen phosphate, and 25g of corn starch) and mix them evenly. The phosphate content is 2.5% (w / w) and the phosphorus content is 0.5% (w / w).

[0152] Positive control feed: Commercially available sucrose ferric hydroxide chewable tablets (Vivre). ® Grind 12.5g of the powder and mix it thoroughly with 487.5g of powdered high-phosphorus feed so that the amount of sucrose hydroxyl iron chewable tablets is 2.5% (w / w) of the total mixture, the phosphate content is 2.5% (w / w), and the phosphorus content is 0.5% (w / w).

[0153] Test feed: Take 12.5g of the dried powder of succinic acid-iron(III) complex prepared according to Example 5, adipic acid-iron(III) complex prepared according to Example 11, and fumarate-iron(III) complex prepared according to Comparative Example 2, and mix them thoroughly with 487.5g of powdered high-phosphorus feed so that the amount of succinic acid-iron(III) complex, adipic acid-iron(III) complex and fumarate-iron(III) complex is 2.5% (w / w) of the total mixture, the phosphate content is 2.5% (w / w), and the phosphorus content is 0.5% (w / w).

[0154] Eight-week-old male Sprague Dawley rats (n=6 per group) were placed in metabolic cages (1 rat per cage). Rats were fasted overnight before placement and fed for 48 hours with one of the following diets: blank diet, high-phosphorus blank diet, positive control diet, and test diet. Total feed intake was recorded. Afterward, the food was removed, and the rats remained in the metabolic cages for 24 hours. Urine was collected from the rats within 72 hours of placement. Urinary phosphorus concentration was measured using a phosphomolybdic acid method inorganic phosphorus assay kit (catalog number: C006-1-1, Nanjing Jiancheng Bioengineering Institute). The total urinary phosphorus concentration was calculated by multiplying the concentration by the urine volume. The phosphorus absorption inhibition rate (%) was calculated using urinary phosphorus normalized to feed intake (mg / g) as the evaluation index, and the iron mass normalized to phosphorus absorption inhibition rate (%) was calculated based on the iron content (%) from phosphate binders in the feed. Results are shown in Table 4.

[0155] Table 4. Metabolic cage experiment data

[0156]

[0157] a Phosphorus absorption inhibition rate (%) = (1-R) 含药高磷饲料 / R 空白高磷饲料 ) × 100%

[0158] b Normalized phosphorus absorption inhibition rate (%) = Phosphorus absorption inhibition rate (%) / Iron from phosphorus binders in feed (%) × 100%

[0159] c Compared with the control group of high-phosphorus diet, p=0.2009;

[0160] * Compared with the control group of high-phosphorus diet, p < 0.05;

[0161] ### Compared with the blank diet, p < 0.001.

[0162] In this embodiment, healthy rats were used, which can metabolize phosphorus normally through the kidneys. The amount of phosphorus excreted in urine is directly related to the amount of phosphorus absorbed in the gastrointestinal tract. In the blank high-phosphorus diet, positive control diet, and test diet used in this embodiment, the amount of phosphorus added was 0.5% (w / w), and the amount of phosphorus binder added was 2.5% (w / w). Since the rats had free access to feed, using urinary phosphorus (mg / g) normalized to feed intake as the evaluation index to calculate the phosphorus absorption inhibition rate can reduce errors.

[0163] As shown in Table 4, after rats were fed a blank high-phosphorus diet, the normalized urinary phosphorus level was significantly higher than that after feeding a blank diet. After rats were fed a high-phosphorus diet with various phosphorus binders, the normalized urinary phosphorus level was lower than that after feeding a blank high-phosphorus diet. This indicates that the phosphorus binders can bind to phosphorus in the rat's gastrointestinal tract and reduce phosphorus absorption.

[0164] Rats fed a high-phosphorus diet supplemented with succinate-iron(III) complex, adipic acid-iron(III) complex, and fumarate-iron(III) complex showed a 43.8%, 37.4%, and 31.6% decrease in urinary phosphorus excretion compared to rats fed a control diet supplemented with a high-phosphorus diet, respectively. These results were significantly better than those from commercially available sucrose ferric hydroxide chewable tablets (Vivre). ® (18.8%). This indicates that the concentration of succinic acid-iron(III) complex, adipic acid-iron(III) complex, and fumarate-iron(III) complex per unit mass is lower than that of commercially available sucrose ferric hydroxide chewable tablets (Vivre). ® It has a stronger phosphorus-binding capacity in the rat gastrointestinal tract, resulting in a significant reduction in urinary phosphorus (p<0.05).

[0165] Because the iron content in the aforementioned added phosphate binders varies, calculating the iron mass-normalized phosphorus absorption inhibition rate (%) based on the iron content (%) from the phosphate binder in the feed provides a better comparison of the phosphorus binding capacity of iron-based phosphate binders per unit mass of iron in the animal's gastrointestinal tract. Succinic acid-iron (III) complex, adipic acid-iron (III) complex, fumarate-iron (III) complex, and commercially available sucrose ferric hydroxide chewable tablets (Vivre) are examples. ® The phosphorus absorption inhibition rates of iron mass-normalized for the following were 68.4%, 68.0%, 50.0%, and 37.6%, respectively. The phosphorus binding capacity per unit mass of iron in animals was: succinic acid-iron(III) complex ≈ adipic acid-iron(III) complex > fumaric acid-iron(III) complex > sucrose ferric hydroxide chewable tablets (Vivre). ® ).

[0166] Succinic acid-iron(III) complex and adipic acid-iron(III) complex both belong to the linear saturated aliphatic dicarboxylic acid-iron(III) complexes described in this invention. In in vitro phosphorus binding experiments, they have similar phosphorus binding capacity per unit mass of iron (greater than 500 mg P / g Fe). Interestingly, in in vivo animal experiments, the phosphorus absorption inhibition rates of iron mass-normalized for succinic acid-iron(III) complex and adipic acid-iron(III) complex are almost the same (68.4% and 68.0%). It can be inferred that similar linear saturated aliphatic dicarboxylic acid-iron(III) complexes have similar structures and similar phosphorus binding capacity per unit mass of iron in vivo. As described in this invention, the molar ratio of iron to dicarboxylic acid in the straight-chain saturated aliphatic dicarboxylic acid-iron(III) complex is close to 1:1. The longer the chain length of the dicarboxylic acid, the lower the iron content per unit mass of the complex. Therefore, the longer the carbon chain of the straight-chain saturated aliphatic dicarboxylic acid-iron(III) complex, the lower the phosphorus binding amount per unit mass (mgP / g complex). More complex is needed to bind the same amount of phosphorus. Therefore, straight-chain saturated aliphatic dicarboxylic acid-iron(III) complex with a chain length of 4 to 8 has better applicability.

[0167] Unexpectedly, the fumarate-iron(III) complex exhibited similar phosphorus binding capacity per unit mass of iron (greater than 500 mgP / gFe) to the succinate-iron(III) complex and the adipic acid-iron(III) complex in in vitro phosphorus binding experiments. However, the phosphorus absorption inhibition rate of the fumarate-iron(III) complex in vivo (normalized to iron mass) (50.0%) was significantly lower than that of the succinate-iron(III) complex and the adipic acid-iron(III) complex (68.4%, 68.0%). This indicates, on the one hand, that the fine structure of the saturated linear aliphatic dicarboxylic acid-iron complex described in this invention differs from that of the fumarate-iron(III) complex with a metal-organic framework structure. On the other hand, it also demonstrates that similar phosphorus binding capacity per unit mass of iron in in vitro aqueous solutions (mgP / gFe) does not equate to similar phosphorus binding capacity per unit mass of iron in vivo. A high phosphorus binding capacity per unit mass of iron in in vitro aqueous solutions (mgP / gFe) does not necessarily mean a high phosphorus binding capacity per unit mass of iron in vivo. Animal experiments have demonstrated the significant advantages of the linear saturated aliphatic dicarboxylic acid-iron(III) complex described in this invention in its development as an oral phosphate binder.

[0168] The dicarboxylic acid-iron(III) complex of this invention has no obvious metallic odor and good thermal stability, and is expected to require fewer excipients and be easy to process when formulating the product. The dicarboxylic acid-iron(III) complex of this invention exhibits strong phosphorus binding specificity, stronger phosphorus binding capacity per unit mass of iron in the body, higher iron utilization rate, lower total iron intake, and the good safety profile of the straight-chain saturated aliphatic dicarboxylic acid contained in the complex, with a low incidence of adverse reactions and high patient compliance.

[0169] According to the examples, the phosphorus absorption inhibition rate (sucrose ferric hydroxide chewable tablets (Vifuri)) ® (18.8%, succinate-iron(III) complex 43.8%) It is estimated that the phosphorus binding amount of 1g of the succinate-iron(III) complex described in this invention in animals is approximately equivalent to that of sucrose ferric hydroxide chewable tablets (Vivre). ® The phosphorus binding amount in animals is 2.5g. According to the drug instructions, sucrose ferric hydroxide chewable tablets (Vivre) ® The maintenance dose is 3 tablets daily (each tablet contains 500mg of iron, each tablet weighs approximately 2.5g, providing a daily iron intake of 1500mg). Another commercially available lanthanum-based phosphorus binder, lanthanum carbonate chewable tablets (Formosinol), is also available. ® The maintenance dose is 3-6 tablets daily (each tablet contains 500mg of lanthanum, each tablet weighs approximately 1.5g, and the daily intake of lanthanum is 1500mg-3000mg). Figure 3This demonstrates tablets (each tablet containing 1g of succinate-iron(III) complex, approximately 250mg of iron, total weight 1.05g, and a daily iron intake of 750mg) prepared according to Example 5 and compressed with approximately 5% excipients, compared with sucrose ferric hydroxide chewable tablets (Vivre). ® ), Lanthanum carbonate chewable tablets (Forslino) ® Compared with the maintenance dose (3 tablets daily), the drug load of the dicarboxylic acid-iron(III) complex of the present invention is significantly lower, the total intake of metal elements is significantly reduced, and the incidence of adverse reactions is low.

[0170] In patients with chronic kidney disease, especially those on dialysis, the kidneys' ability to excrete phosphorus decreases, leading to elevated blood phosphorus levels. This can cause damage to bones, blood vessels, the heart, and soft tissues. Phosphate binders can bind to phosphorus in food in the gastrointestinal tract, reducing phosphorus absorption and thus lowering blood phosphorus levels, thereby preventing and improving a series of subsequent complications. Controlling blood phosphorus can directly prevent hyperphosphatemia. Long-term high phosphorus levels increase the calcium-phosphorus product, causing calcium and phosphorus to deposit in muscles, skin, joints, and internal organs, leading to soft tissue calcification. Lowering blood phosphorus can reduce this deposition and effectively prevent soft tissue calcification. High blood phosphorus inhibits the production of active vitamin D, causing hypocalcemia, which in turn stimulates excessive secretion of parathyroid hormone, leading to secondary hyperparathyroidism. At the same time, excessively high parathyroid hormone can excessively dissolve bone, leading to renal osteodystrophy, bone pain, fractures, osteomalacia, osteoporosis, and other forms of bone dystrophy. Phosphate binders, by controlling blood phosphorus, can reduce the excessive workload of the parathyroid glands, thereby protecting bones and improving bone diseases. Furthermore, high blood phosphorus levels can cause vascular calcification, heart valve calcification, and myocardial stiffness, significantly increasing the risk of cardiovascular diseases such as coronary heart disease, heart failure, arrhythmia, and even sudden death. Stabilizing blood phosphorus levels can slow down vascular calcification and reduce the risk of cardiovascular death. Simply put, decreased renal phosphorus excretion leads to elevated blood phosphorus levels, which in turn causes hyperphosphatemia, secondary hyperparathyroidism, renal osteodystrophy, soft tissue calcification, and cardiovascular diseases. Using phosphate binders to reduce phosphorus absorption and control blood phosphorus levels can prevent and improve these conditions.

[0171] The above description is only a part of the preferred embodiments of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A linear saturated aliphatic dicarboxylic acid-iron complex as an oral phosphate binder, characterized in that, The molar ratio of iron to the straight-chain saturated aliphatic dicarboxylic acid-iron complex is 1:0.8~1.

2. The complex is prepared by reacting a ferric salt and a straight-chain saturated aliphatic dicarboxylic acid salt in a solvent without using any pH adjusters. The mass percentage of iron in the complex is 20%~30%. The straight-chain saturated aliphatic dicarboxylic acid is succinic acid or adipic acid. The solvent is water. The straight-chain saturated aliphatic dicarboxylic acid salt is an alkali metal salt or ammonium salt of the same compound. The ferric salt is selected from any one or more of ferric chloride and ferric nitrate.

2. The method for preparing the linear saturated aliphatic dicarboxylic acid-iron complex as an oral phosphate binder according to claim 1, characterized in that, The process includes the following steps: mixing a straight-chain saturated aliphatic dicarboxylic acid salt with a ferric salt in a solvent, stirring until the reaction is complete, separating and washing the precipitate, and drying to obtain a straight-chain saturated aliphatic dicarboxylic acid-iron complex.

3. The method for preparing the linear saturated aliphatic dicarboxylic acid-iron(III) complex as an oral phosphate binder according to claim 2, characterized in that, The stirring temperature should be below 60℃.

4. The method for preparing the linear saturated aliphatic dicarboxylic acid-iron(III) complex as an oral phosphate binder according to claim 2, characterized in that, The stirring temperature is 20~40℃.

5. The method for preparing the linear saturated aliphatic dicarboxylic acid-iron(III) complex as an oral phosphate binder according to claim 2, characterized in that, The reaction time is 2 to 8 hours.

6. The method for preparing the linear saturated aliphatic dicarboxylic acid-iron complex as an oral phosphate binder according to claim 2, characterized in that, The molar ratio of ferric salt to linear saturated aliphatic dicarboxylic acid salt is 1:0.5~10.

7. The use of the linear saturated aliphatic dicarboxylic acid-iron complex as an oral phosphate binder according to claim 1 in the preparation of oral phosphate binders.

8. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the linear saturated aliphatic dicarboxylic acid-iron complex as an oral phosphate binder as described in claim 1, and the dosage form of the pharmaceutical composition includes capsules, tablets, granules, suspensions, or powders.

9. The pharmaceutical composition according to claim 8, characterized in that, The pharmaceutical composition is for oral administration.

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