Method for preparing iron complexes

Abstract

A method for preparing an iron hydroxide product is provided. The method includes adding a first base solution to a solution of ferric salt to obtain a mixture A having a pH of 2.7 to 2.8, adding a second base solution to mixture A to obtain a crude iron hydroxide suspension having a pH of 2.8 to 3.8, and adding a third base solution to adjust the pH of the crude iron hydroxide suspension to 5 to 9, followed by purifying and concentrating the crude iron hydroxide suspension to obtain a purified polynuclear iron hydroxide suspension containing polynuclear iron hydroxide. Nanoiron complexes, such as iron hydroxide carbohydrate complexes, and methods for preparing them are also provided.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of priority from Chinese Patent Application Nos. 202011055789.2 and 202011055787.3, both filed on September 29, 2020. The contents and disclosures of both applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Iron plays an important role in oxygen transport in humans. Iron deficiency is the most common form of malnutrition in humans, leading to anemia. Patients with advanced renal failure suffer from severe iron deficiency anemia. The survival rate of such patients is closely related to their iron supply.

[0003] Iron infusion is the first choice for caring for such patients. Conventional iron supplements, such as ionic iron or small-molecule iron, have a high oxidation potential and cause oxidative damage to organs. Over the past 30 years, carbohydrate-coated iron hydroxide nanoparticles have become the mainstream source of iron infusion. Among these, iron hydroxide sucrose complex nanoparticles are the first choice for commercial iron infusion due to their rapid onset and minimal side effects.

[0004] To optimize safety and efficacy, each iron-sucrose complex nanoparticle must have an appropriate particle size: if the nanoparticles are too small, the iron will be released too quickly, resulting in serious oxidative damage; if the nanoparticles are too large, the release will be slow, increasing the likelihood of serious allergic side effects.

[0005] Useful iron hydroxide sucrose complex nanoparticles have been found to have molecular weights ranging from 32,000 Daltons to 60,000 Daltons, which is the molecular weight range required by the United States Pharmacopeia for iron nanoparticle products.

[0006] Iron hydroxide sucrose complexes comprise polymeric nanoparticles. The stability and particle size of polymeric nanoparticles are closely related to processing conditions, such as temperature, reaction rate, and acid-base conditions. Preparation remains challenging. Current commercial iron sucrose complexes are prepared by low-temperature processes that require expensive explosion-proof equipment. As shown in certain patents, when processing temperatures are above 20°C, the nanoiron sucrose complexes prepared in this manner have molecular weights exceeding 80,000 daltons, rendering the product useless.

[0007] The rate of iron release is another quality-defining characteristic for nanoiron sucrose complexes. Too rapid a release would cause oxidative damage as a side effect. Vifor Pharma Group, a manufacturer of nanoiron sucrose injectable products, mandates as a quality control that the rate of iron release must be within 20 minutes under acidic conditions with vitamin C. Currently, no reliable preparation process that meets this important quality requirement has been found in any patent covering sucrose-coated iron hydroxide.

[0008] Patent Document 1 discloses a method for preparing polynuclear iron hydroxide sucrose complexes. The polynuclear iron hydroxide component is prepared at a low temperature of 5°C to 20°C. The polynuclear iron hydroxide component is then chelated with sucrose at an elevated temperature of 106°C to 125°C, resulting in a product with a molecular weight outside the range required by USP.

[0009] Patent Document 2 discloses a method for preparing an iron-sucrose complex solution with a low heavy metal content. The specific steps are as follows: 1. Add ferric chloride to an aqueous sodium carbonate solution at 50-80°C while stirring, and allow the ferric chloride to react until the solution turns black. The precipitate is then removed by filtration. 2. Cool the filtrate to 0-5°C and stir for 4-8 hours. Add sodium carbonate solution dropwise until the pH of the reaction mixture reaches 7-9. 3. Add sodium hydroxide to the iron hydroxide colloid to adjust the pH of the reaction mixture to 10 or higher. Add sucrose to the mixture and heat the reaction solution until it boils to obtain a nano-iron-sucrose complex. Problems with the process described in Patent Document 2 include long processing times and low temperatures, making it costly. Furthermore, the rapid formation of the iron complex makes it difficult to control the turbidity point, an important quality indicator.

[0010] Patent Document 3 discloses an environmentally friendly method for preparing iron-sucrose complexes. The process is as follows: (1) Prepare a 0.5% to 5% by weight solution of FeCl3·6H2O and Na2CO3, add the Na2CO3 solution to the FeCl3·6H2O solution using a peristaltic pump at 0°C to 30°C for a supply time of 0.5 to 3 hours, and stir for 1 hour. The resulting suspension is centrifuged to obtain an Fe(OH)3 cake. The mixing / centrifugation / washing with purified water cycle is repeated four times to obtain a purified Fe(OH)3 cake. The iron content of the Fe(OH)3 cake is measured (FeCl3·6H2O and Na2CO3). (2) adding sucrose to the Fe(OH)3 obtained above in a ratio of Fe:sucrose = 1:13.5-16.5, and heating the resulting mixture at 85-140°C and pH 8-13 for 2-18 hours; cooling the mixture to obtain a nano-iron sucrose complex; and (3) treating the complex with D301 anion exchange resin followed by D113 cation exchange resin, adjusting the pH to 10.2-11.0, and filtering through a 0.8 μm ultrafiltration membrane to obtain the final nano-iron sucrose product. The process described in Patent Document 3 is costly due to the required low temperatures, high pressures, and use of ion exchange resins for purification.

[0011] Other known iron products include ferric citrate, ferric pyrophosphate citrate, and ferric gluconate. See, for example, U.S. Patent Nos. 5,629,999, 5,629,999, 5,629,999, 5,629,999, and 5,629,999. Each of these products has drawbacks, such as low water solubility, low iron content, and inefficient processing, which significantly limit their applications. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] Chinese Patent Application Publication No. 1853729 [Patent Document 2] Chinese Patent Application Publication No. 109893540 [Patent Document 3] Chinese Patent No. 103059072 [Patent Document 4] U.S. Patent No. 9,624,155 [Patent Document 5] U.S. Patent No. 7,816,404 [Patent Document 6] U.S. Patent No. 7,767,851 [Patent Document 7] U.S. Patent No. 7,005,531 Summary of the Invention [Problem to be solved by the invention]

[0013] There is a need to develop cost-effective methods for preparing iron products suitable for pharmaceutical and nutritional use. [Means for solving the problem]

[0014] To address the problems with current low-temperature processes discussed above, the present invention provides an efficient method for preparing iron hydroxide complexes at ambient conditions with superior properties, including high aqueous solubility, high iron content, and high bioavailability.

[0015] Thus, one aspect of the present invention relates to a method for preparing an iron hydroxide product, which includes the steps of: (1) adding a first base solution to a solution of a ferric salt to obtain a mixture A having a pH of 2.7 to 2.8; (2) adding a second base solution to mixture A to prepare a crude iron hydroxide suspension having a pH of 2.8 to 3.8; and (3) adding a third base solution to adjust the pH of the crude iron hydroxide suspension to 4.5 to 9.5 (e.g., 5 to 9), followed by purification and concentration to obtain a purified polynuclear iron hydroxide suspension containing polynuclear iron hydroxide as an exemplary product of the present invention.

[0016] For example, conventional methods, such as washing with water and then concentrating by removing the water, followed by purification, yield an iron hydroxide suspension with an iron hydroxide concentration of 3% to 16% by weight. After purification, the chlorine content is reduced to less than 1% (e.g., less than 0.1% and less than 0.025%). The purification step reduces the free Fe 3+ and Fe 2+ also removes iron, which contributes to iron oxidation damage in the patient's organs. Free iron cations are also the source of an undesirable metallic taste in the final product, e.g., oral formulations.

[0017] Preferably, mixture A is equilibrated for 1 to 15 minutes before the addition of the second base, and the crude iron hydroxide suspension is equilibrated for 2 to 60 minutes before the addition of the third base, both at ambient temperature, e.g., 20 to 30°C, and 25°C.

[0018] Typically, the first base solution, the second base solution, and the third base solution are each independently added at a temperature of 15°C to 50°C (e.g., 20°C to 40°C, 20°C to 30°C, and 22°C to 27°C). The first base solution, the second base solution, and the third base solution can independently be aqueous solutions of carbonates, such as NaHCO3, Na2CO3, (NH4)2CO3, and K2CO3. A preferred solution is an aqueous Na2CO3 solution having a mass fraction of 1% to 25% (e.g., 3% to 20%, 5% to 15%, and 10%). Furthermore, the first base solution, the second base solution, and the third base solution can be the same or different.

[0019] Suitable ferric salts include Fe2(SO4)3, Fe(NO3)3, FeCl3, and hydrates thereof. A preferred ferric salt is FeCl3 (e.g., FeCl3·6H2O) with a mass fraction of 5% to 60%, preferably 15% to 25%.

[0020] In some embodiments, the method further comprises the steps of (i) mixing the purified polynuclear iron hydroxide suspension with a carbohydrate to obtain a carbohydrate mixture; (ii) adjusting the pH of the carbohydrate mixture to 7.5-13, or 9.5-13.5 (e.g., 10-13.5); and (iii) heating the pH-adjusted carbohydrate mixture to a temperature of 60°C-125°C (preferably 75-95°C, more preferably 80-95°C) to produce an iron hydroxide-carbohydrate complex suspension, wherein the iron to carbohydrate mass ratio is (1-1100):100, and the iron hydroxide product is an iron hydroxide-carbohydrate complex.

[0021] Exemplary carbohydrates include monosaccharides, disaccharides, oligosaccharides, polysaccharides, hydrolyzed polysaccharides, and any combination thereof. In a preferred embodiment, the carbohydrate is sucrose, and Fe 3+ The mass ratio of sucrose to sugar is 1:(10-20), for example, 1:(13-17).

[0022] Optionally, the pH value of the carbohydrate mixture is adjusted by adding a fourth base which is a hydroxide solution selected from the group consisting of NH4OH solution, KOH solution, and NaOH solution, the hydroxide solution having a mass proportion of 5% to 50%, preferably 10% to 25%.

[0023] In one example, the pH value of the carbohydrate mixture is adjusted to 9.5 to 13.5 (e.g., 10 to 13.5), and the pH-adjusted carbohydrate mixture is heated at 80°C to 125°C (e.g., 85°C to 95°C) for 1 hour to 50 hours.

[0024] After the complex is formed, a pH adjuster is optionally used to adjust the pH value of the complex to 5.5 to 11.1, 10.5 to 11.2, or 6.5 to 7.5. Suitable pH adjusters include HCl, NaOH, citric acid, oxalic acid, fumaric acid, tartaric acid, succinic acid, malic acid, ascorbic acid, phosphoric acid, pyrophosphoric acid, and glycolic acid.

[0025] In another example, the pH value of the carbohydrate mixture is adjusted to 7.5-13 (e.g., 9-12.5), and the pH-adjusted carbohydrate mixture is heated to 65°C-121°C, preferably 80°C-95°C, for 0.2 hours-30 hours, and the mass ratio of iron to carbohydrate is (1-264):24.

[0026] The iron hydroxide carbohydrate complexes thus prepared have properties suitable for human consumption in the treatment of iron deficiency-related disorders. Desirable properties include one or more of the following characteristics: a weight-average molecular weight of 30,000 to 60,000; a reaction rate (T75) with ascorbic acid of less than 35 minutes; no free ferric ions; a solubility in water of 20% by weight or more (e.g., 50% or more, 20% to 50%, and 35% by weight); an iron content by dry weight of 10% to 47% (e.g., 15% to 47%); and a chloride ion content of less than 1% (e.g., less than 0.1%).

[0027] In another embodiment, the method of the present invention further comprises the steps of (i) mixing the purified polynuclear iron hydroxide suspension with citric acid, a citrate salt, or a combination thereof to obtain a citrate mixture, and (ii) heating the citrate mixture at a temperature of 40°C to 105°C (e.g., 45°C to 95°C and 55°C to 65°C) for 2 minutes to 10 hours (e.g., 2 minutes to 180 minutes and 5 minutes to 30 minutes) to produce a ferric citrate complex suspension containing an iron hydroxide citrate complex, wherein the molar ratio of iron to citrate is 1:(0.3-5), preferably 1:(0.6-1.5), and the iron hydroxide product is an iron hydroxide citrate complex. Compared to currently available commercial products, iron hydroxide citrate complexes surprisingly have superior properties, such as a solubility in water of 20% by weight or more (e.g., 50% by weight or more), a high iron content (e.g., 5% to 35% and 12% to 25% by dry weight), and the absence of free ferric ions.

[0028] In yet another embodiment, the method further comprises: (a) mixing the purified polynuclear iron hydroxide suspension with a solution containing (i) citric acid or a citrate salt, and (ii) pyrophosphoric acid or a pyrophosphate salt to obtain a pyrophosphate mixture; and (b) heating the pyrophosphate mixture at a temperature of 40°C to 105°C (e.g., 55°C to 65°C) for 5 minutes to 10 hours (e.g., 25 minutes to 55 minutes) to produce a ferric citrate pyrophosphate suspension, wherein the molar ratio of iron:citrate:pyrophosphate is 1:(0.3-3):(0.3-3), and the iron hydroxide product is an iron hydroxide citrate pyrophosphate complex having a solubility in water of 20% by weight or more (e.g., 50% by weight or more) and containing 3% to 35% by dry weight (e.g., 5% to 20%) iron.

[0029] In yet another embodiment, the method further comprises the steps of (a) mixing the purified polynuclear iron hydroxide suspension with a carboxylated carbohydrate to obtain a carboxylated carbohydrate mixture, and (b) heating the carboxylated carbohydrate mixture at a temperature of 50°C to 125°C (e.g., 65°C to 125°C, 55°C to 75°C, and 65°C to 75°C) for 5 minutes to 10 hours (e.g., 25 minutes to 55 minutes) to produce a ferric carboxylated carbohydrate suspension, wherein the molar ratio of iron to carboxylated carbohydrate is 1:(0.3 to 5), preferably 1:(0.5 to 1.5), and the iron hydroxide product is an iron hydroxide carboxylated carbohydrate complex. Exemplary carboxylated carbohydrates are gluconate and other carboxylated disaccharides, oligosaccharides, and polysaccharides.

[0030] Furthermore, the method of the present invention further comprises the steps of (a) mixing the purified polynuclear iron hydroxide suspension with a polyvalent anion to obtain a polyvalent anion mixture, (b) adjusting the pH value of the polyvalent anion mixture to 2 to 13, preferably 3 to 9, and (c) heating the pH-adjusted polyvalent anion mixture to a temperature of 40°C to 125°C, preferably 50°C to 95°C, to prepare a nano-ferric complex suspension, wherein the mass ratio of iron to polyvalent anion is (1 to 1100):100, and the iron hydroxide product is a nano-ferric complex.

[0031] Any complex suspensions thus prepared can be dried by conventional drying methods, such as spray drying. In either liquid or dry form, the iron hydroxide carbohydrate complexes can be formulated into drops, oral liquids, suspensions, injectable solutions, powders, capsules, tablets, or lozenges for treating iron deficiency anemia in humans or animals.

[0032] Iron hydroxide products prepared from any of the above-described methods are also within the scope of the present invention, including pharmaceutical and nutritional compositions containing the iron hydroxide products of the present invention and a pharmaceutically or nutritionally acceptable carrier.

[0033] Further within the scope of the present invention is a method for treating an iron deficiency-related disorder or hyperphosphatemia by administering to a subject in need thereof a pharmaceutically effective amount of an iron hydroxide product as described above.

[0034] The details of several embodiments of the invention are set forth in the following description. Other features, objects, and advantages of the invention will also become apparent from the specification, drawings, and appended claims. [Brief explanation of the drawings]

[0035] [Figure 1] 1 is a gel permeation chromatograph (GPC) for determining the molecular weight of the iron hydroxide carbohydrate complex prepared in Example 1 below. [Figure 2] FIG. 1 is a structural diagram of an exemplary nanoparticle of an iron hydroxide carbohydrate complex of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0036] One of the goals of the present invention is to overcome the problems of the current slow and costly low temperature processes described in the Background section above. Furthermore, current preparations at room temperature result in undesirably high molecular weight iron hydroxide sucrose complexes.

[0037] Another object of the present invention is to overcome the problem of residual amounts of ferric and chloride ions remaining in the iron hydroxide carbohydrate complex product.

[0038] Therefore, the present invention provides a cost-effective method for the preparation of nano-iron hydroxide complexes.

[0039] The first method of the present invention comprises the following steps. (1) adding a first aqueous base solution to an aqueous iron salt solution and mixing them uniformly until the pH value reaches 2.7 to 2.8; (2) adding a first aqueous base solution to the mixture obtained in step (1) and mixing them uniformly to obtain a reaction mixture having a pH value of 2.8 to 3.8, thereby obtaining a crude iron hydroxide suspension; (3) adding the first aqueous base solution to the crude iron hydroxide suspension and mixing them uniformly to obtain an iron hydroxide suspension having a pH value of 4.5 to 9; (4) collecting the iron hydroxide particles from the suspension, followed by purification and concentration to obtain a purified polynuclear iron hydroxide wet cake;

[0040] The second method of the present invention comprises the steps of adding a carbohydrate to purified polynuclear iron hydroxide and mixing uniformly to obtain a mixture, adjusting the pH of the mixture to 9.5 to 13.5 with the aqueous base solution from step 2, and heating the pH-adjusted mixture at 85°C to 125°C for 1 hour to 50 hours to obtain an iron hydroxide-carbohydrate complex.

[0041] The third method of the present invention includes the steps of adding a carbohydrate to polynuclear iron hydroxide and uniformly mixing them to obtain mixture B, adjusting the pH value of mixture B to 7.5 to 13 with the base solution of step 2, and then heating at 60°C to 125°C for 0.2 to 30 hours to obtain an iron hydroxide-carbohydrate complex, wherein the iron to carbohydrate ratio is (1 to 1100):100.

[0042] The fourth method of the present invention comprises the step of preparing a nano-iron hydroxide complex suspension containing an iron hydroxide polyvalent anion complex or an iron hydroxide carboxylated carbohydrate complex by mixing a purified polynuclear iron hydroxide suspension with a polyvalent anion or a carboxylated carbohydrate at a temperature of 45°C to 125°C (e.g., 55°C to 95°C, 75°C to 95°C, 45°C to 65°C, and 65°C to 75°C) for 2 minutes to 6 hours.

[0043] Suitable multivalent anions include citrate, tartarate, succinate, fumarate, malate, glyceryl phosphate, any salt thereof, and any combination thereof. These multivariant anions can be used in combination with pyrophosphate.

[0044] Exemplary carboxylated carbohydrates are gluconates and other carboxylated disaccharides and polysaccharides. Gluconic acid or any water-soluble gluconate salt (e.g., an alkali D-gluconate salt, such as sodium D-gluconate) can be used in the preparation.

[0045] The advantages of the above method are summarized below. (1) Iron hydroxide carbohydrate complexes are prepared at room temperature (e.g., 15°C-40°C, 20°C-35°C, 22°C-27°C, and 25°C), thus avoiding low-temperature and costly routes. Temperature is also precisely controlled by a three-step pH titration process to prepare the Fe(OH)3 suspension. (2) The method is a low-chloride process, which also avoids contamination with heavy metals. The chloride content is less than 0.1% by weight of the complex. (3) The iron hydroxide carbohydrate complexes prepared in this manner contain no residual free ferric iron, thus minimizing potential oxidative damage to the human body. At high iron content, each complex contains an iron hydroxide core surrounded by a carbohydrate shell at an appropriate carbohydrate:iron ratio. No residual free ferric iron is detectable in these complexes. (4) Iron hydroxide sucrose complex is an example of an iron hydroxide carbohydrate complex prepared according to the present invention at room temperature. The weight average molecular weight of this complex is 30,000 to 60,000 daltons, which is a desirable molecular weight range for providing rapid iron release and fast onset with a high safety margin. (5) Each of the iron hydroxide sucrose complexes has a T75 reaction rate with ascorbic acid of 35 minutes or less. The iron hydroxide sucrose complexes meet the required qualities of rapid onset and safety. (6) Iron hydroxide sucrose complexes can be basic (pH above 7) or neutral (pH around 7). Iron hydroxide sucrose complexes are stable and can be sterilized at high temperatures. (7) The iron hydroxide carbohydrate complex can be in liquid or solid form and is conveniently formulated into any liquid or solid dosage form. (8) Unlike certain known processes, the present process does not require organic solvents, avoiding contamination with organic residues. (9) Each of the iron hydroxide complexes has high aqueous solubility (e.g., 20% by weight or more and 50% by weight or more), making them suitable for the development of high-dose liquid dosage forms (e.g., drops containing 10% by weight of iron). (10) The method can be carried out under mild conditions without the need for refrigeration, pressurization, or explosion-proof equipment, facilitating industrial adoption of the method. Furthermore, impurities are virtually absent, resulting in high bioavailability. This method can be used to develop improved iron-supply products for treating iron-deficiency anemia or for phosphate removal in renal dialysis patients.

[0046] The following specific embodiments further illustrate the method of the present invention, but these embodiments should not be construed as limiting the present invention. Modifications and substitutions of the method, steps, or conditions of the present invention without departing from the essence of the present invention are within the scope of the present invention.

[0047] Iron hydroxide carbohydrate complex In both the first and second methods described above, the first aqueous base solution can be an aqueous solution of a carbonate or bicarbonate, such as NaHCO3, Na2CO3, (NH4)2CO3, and K2CO3. A preferred base is Na2CO3. The mass ratio of the base in the aqueous solution is usually 5% to 25%, preferably 10% to 15%. Other steps are the same as in embodiment 1. The carbonate or bicarbonate includes their anhydrous and hydrated forms. Examples are Na2CO3·H2O, Na2CO3·7H2O, and Na2CO3·10H2O.

[0048] The iron salt solution can be an aqueous solution of Fe2(SO4)3, Fe(NO3)3, FeCl3, or any combination thereof. Iron salts include anhydrous and hydrated forms thereof, such as FeCl3·6H2O and Fe(NO3)3·9H2O. Preferred salts are FeCl3, including FeCl3·6H2O. The weight percentage of the iron salt solution can be 5% to 60% (e.g., 15% to 25%).

[0049] The preferred carbohydrate in the first method is sucrose. 3+ The mass ratio of sucrose to sugar is 1:(10 to 20), preferably 1:(13 to 17). Preferred carbohydrates in the second method include monosaccharides, disaccharides, oligosaccharides, polysaccharides, polysaccharide hydrolyzed syrup, and any combination thereof.

[0050] The aqueous base solution in step 2 can be an aqueous solution of a hydroxide compound, such as NH4OH, KOH, and NaOH, preferably NaOH, in a mass proportion of 5% to 50% (e.g., 10% to 25%) in the aqueous solution.

[0051] Regarding the first method, the pH of the iron hydroxide-carbohydrate complex obtained in step 2 can be adjusted to 5.5 to 11.1 (e.g., 10.5 to 11.1, or 6.5 to 7.5) using a pH adjuster. Suitable examples of pH adjusters include HCl, NaOH, and organic or inorganic acids selected from the group consisting of citric acid, oxalic acid, fumaric acid, tartaric acid, succinic acid, malic acid, ascorbic acid, phosphoric acid, pyrophosphoric acid, and glycolic acid. Regarding the second method, carbohydrate is added to polynuclear iron hydroxide and mixed uniformly to obtain mixture B. The pH of mixture B is then adjusted to 9.5 to 12.5, and the mixture is reacted at 65°C to 95°C for 0.2 to 30 hours to obtain an iron hydroxide-carbohydrate complex having an iron / sugar ratio of (1 to 264):24.

[0052] The iron hydroxide carbohydrate complexes thus prepared exist in either liquid or solid form. For solid use, a drying process such as spray drying may be included. The iron hydroxide carbohydrate complexes thus prepared can be formulated into drops, oral liquids, injectable solutions, powders, capsules, suspension dosage forms, or tablets for the treatment of iron deficiency anemia in humans or animals.

[0053] Some iron hydroxide carbohydrate complexes (e.g., iron hydroxide sucrose complexes prepared by the first method) have one of the following favorable characteristics: a weight-average molecular weight of 30,000 to 60,000 daltons; a T75 reaction rate with ascorbic acid of 35 minutes or less; the absence of residual free ferric iron; high stability at high pH or neutral conditions; and the ability to be sterilized at high temperatures. Other iron hydroxide carbohydrate complexes (e.g., prepared by the second method) have a water solubility of 20% to 50%, an iron content of 15% to 47% by dry weight, and a chloride ion content of less than 1% (e.g., less than 0.1% and less than 0.025%).

[0054] Iron hydroxide products prepared by any of the above methods are also within the scope of the present invention. As shown in Figure 2, each of the iron hydroxide products has a polynuclear iron hydroxide core and a shell formed of carbohydrates, polyvalent anions, or carboxylated carbohydrates.

[0055] Also within the scope of the present invention is a method for treating an iron deficiency-related disorder (e.g., anemia) by administering to a subject in need thereof an effective amount of an iron hydroxide product, or a pharmaceutical composition containing an iron hydroxide product.

[0056] The term "treating" refers to the application or administration of a compound to a subject to cure, alleviate, relieve, alter, treat, ameliorate, or affect a disease, condition, or predisposition. An "effective amount" refers to the amount of product necessary to produce the desired effect in a subject. As recognized by those skilled in the art, effective amounts vary depending on the route of administration, excipient usage, and the possibility of concurrent use with other therapeutic treatments. Dosage levels for the iron hydroxide products of the present invention are on the order of 1 mg / day to 200 mg / day (e.g., 150 mg / day, 45 mg / day, 15 mg / day, 2 mg / day to 45 mg / day, 3 mg / day to 30 mg / day, and 5 mg / day to 25 mg / day). The specific dose level for a particular patient will vary depending on numerous factors, including age, weight, general health, sex, diet, time of administration, rate of excretion, and the severity of the iron deficiency.

[0057] The term "carbohydrate" refers to a carbohydrate having the general formula (CHO) n(where n is 3 to 300) refers to an aldehyde or ketone compound substituted with multiple hydroxyl groups. Carbohydrates include monosaccharides (n = 3 to 10), disaccharides (n = 8 to 14, e.g., 12; having two monosaccharide units), oligosaccharides (n = 15 to 59; i.e., having three to nine monosaccharide units), and polysaccharides (i.e., having 10 or more monosaccharide units). Monosaccharides cannot be decomposed into simpler sugars by hydrolysis. Monosaccharides constitute the building blocks of disaccharides, oligosaccharides, and polysaccharides. Examples include glyceraldehyde, dihydroxyacetone, erythrose, threose, arabinose, ribose, xylose, ribulose, xylulose, glucose (dextrose), fructose, galactose, ribose, allose, altrose, gulose, idose, mannose, talose, psicose, sorbose, tagatose, mannoheptulose, sedoheptulose, 2-keto-3-deoxy-manno-octonate, and sialose. Examples of disaccharides include sucrose, maltose, isomaltose, lactose, trehalose, cellobiose, chitobiose, rutinose, and rutinulose. The term "carboxylated carbohydrate" refers to a carbohydrate having a carboxyl group (-COOH or -COO). - Carboxylated carbohydrates can be prepared by oxidizing the corresponding parent carbohydrate.

[0058] The term "water solubility" refers to the maximum concentration of dispersed nanoparticles in water that simultaneously exist in equilibrium with colloidal solubility and agglomerates. See, e.g., Doblas, et al., Nano Lett. 19, 5246-52 (2019). The water solubility of the iron product of the present invention is the maximum concentration at which the iron product is uniformly dispersed in water as a clear liquid without precipitation or cloudiness.

[0059] Without further elaboration, it is believed that one skilled in the art can, based on the preceding description, utilize the present invention to its fullest extent. The following examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference in their entirety.

[0060] Examples illustrating methods for preparing iron hydroxide complexes and evaluating the effectiveness of these complexes are provided below. [Example]

[0061] Example 1: Iron hydroxide sucrose complex 1 The complex was prepared according to the following steps.

[0062] 1.1. 75 g of FeCl3·6H2O was dissolved in water to obtain a 15% ferric chloride solution (500 g). 1.2. 45 g of sodium carbonate was mixed in water to obtain a 10% by mass Na2CO3 aqueous solution (450 g).

[0063] 2. Preparation of Fe(OH)3 suspension: 2.1. A 10% aqueous solution of Na2CO3 was added to a 15% ferric chloride solution and mixed until the pH of the mixture reached 2.7. At this point, a large amount of carbon dioxide was generated and the color of the reaction solution changed from light brown to dark brown, but the solution remained transparent. 2.2. 10% Na2CO3 aqueous solution was added to the clear solution and mixed evenly to obtain a reaction mixture with a pH of 3.8. This was a crude iron hydroxide suspension. At this point, a large amount of particles precipitated from the solution. 2.3. The remaining 10% Na2CO3 aqueous solution was added to the crude iron hydroxide suspension and mixed uniformly to obtain an iron hydroxide suspension with a pH value of 5. 2.4. The pH 5 iron hydroxide suspension was collected in a 10 L container, and 9 L of water was added while stirring, and the mixture was allowed to settle. After removing the upper clear aliquot, the remaining mixture was centrifuged, and water was repeatedly added during centrifugation. The brown precipitate was collected to obtain polynuclear iron hydroxide. This iron hydroxide had a chloride ion content of less than 0.05%.

[0064] 3. In a 1 L container, the polynuclear iron hydroxide thus obtained was mixed with 240 g of sucrose under stirring. The pH value of the resulting mixture was adjusted to 12 using 20% sodium hydroxide solution. The reaction was carried out at 100°C and pH 12 for 21 hours to obtain an iron hydroxide sucrose complex.

[0065] The molecular weight of the iron hydroxide sucrose complex thus obtained was determined by gel permeation chromatography ("GPC") as described below.

[0066] A. Equipment and Test Agents: Agilent 1100 HPLC equipped with a Shodex refractive index detector. Shodex P-82 pullulan was used as a standard for molecular weight.

[0067] B. Method: B.1 Chromatographic conditions: Chromatography columns: Waters Ultrahydrogel™ 7.8 mm x 30 cm columns (pore sizes of 1000 Å and 120 Å, respectively). Two columns were connected in series. Mobile phase: Phosphate buffer solution (7.17 g of disodium hydrogen phosphate dodecahydrate, 2.76 g of disodium hydrogen phosphate, and 0.2 g of sodium azide in 1000 ml of water). Detector temperature: 45°C. Column temperature: 45°C ± 2°C. Flow rate: 0.5ml. Injection volume: 25 μl.

[0068] B.2 Sample Measurement: A test solution was prepared by adding a predetermined amount of sample to the mobile phase solution and then filtering. 25 μl of the test solution was injected for analysis. The data was processed using special software for GPC (HW-2000). The weight average molecular weight (M w ), number average molecular weight (M n ), and D were calculated from a calibration curve obtained from data generated by testing standards under identical conditions.

[0069] B.3 GPC spectrum of test results: The molecular weight according to Shodex standards was 47,100 daltons.

[0070] The weight-average molecular weight of the iron hydroxide sucrose complex in Example 1 was 46,700 daltons.

[0071] Example 2: Iron hydroxide sucrose complex 2 The complex was prepared as follows:

[0072] A.1. A 15% ferric chloride solution was prepared by dissolving 225 g of FeCl3·6H2O in water to obtain 1500 g of solution.

[0073] 2. 135 g of sodium carbonate was dissolved in water to obtain 1350 g of a 10% mass Na2CO3 aqueous solution.

[0074] B. A polynuclear iron hydroxide suspension was prepared using the ferric chloride solution and Na2CO3 solution from step A according to the three-step titration procedure described in Example 1 above.

[0075] C. The polynuclear iron hydroxide thus obtained was mixed with 720 g of sucrose in a 2 L container. The pH value of the resulting mixture was adjusted to 12 with 20% sodium hydroxide solution, and then heated at 90°C and pH 12 for 42 hours to obtain iron hydroxide sucrose complex 2.

[0076] Example 3: Iron hydroxide sucrose complex 3 The complex was prepared following a procedure similar to that described in Example 1 above.

[0077] A.1. A 15% ferric chloride solution (5000 g) was obtained by dissolving 750 g of FeCl3·6H2O in water.

[0078] 2. 450g of aqueous sodium carbonate solution was used to obtain 10% Na2CO3 solution (4500g).

[0079] B. Polynuclear iron hydroxide was prepared using the ferric solution obtained in step A above and Na2CO3 according to a three-step titration procedure.

[0080] C. Polynuclear iron hydroxide was mixed with 2400 g of sucrose. The resulting mixture was adjusted to pH 12 with 20% sodium hydroxide solution and heated at 95°C for 32 hours to obtain iron hydroxide sucrose complex 3. This complex had a pH of 12.

[0081] evaluation (a) Free iron content (i.e., Fe) of iron hydroxide sucrose complexes 1, 2, and 3 3+ and Fe 2+ ), (b) chloride ion content, and (c) reaction rate T75 to ascorbic acid were evaluated.

[0082] (a) Free iron (i.e., Fe 3+ and Fe 2+ ) detection: (1) Iron 3+ A sample (5 mL) of the complex was mixed with 1 mL of 2 mol / L aqueous ammonia solution for 1 minute and observed for the presence of a brown precipitate. If a precipitate is observed, free Fe 3+ Ions are present in the sample. (2) Iron 2+ (a) Potassium ferricyanide solution: 1 g of potassium ferricyanide was weighed out and water was added until the resulting solution reached 10 mL. (b) Acetic acid-sodium acetate buffer solution (pH 5.6): 12 g of sodium acetate was weighed and dissolved in 50 mL of distilled water, and 0.66 mL of acetic acid was added, followed by adding water to make up to 100 mL. (c) The complex suspension (5 mL) was diluted with water to 50 mL to obtain an evaluation sample. Two types of test solutions, namely, a blank solution and an evaluation solution, were prepared.

[0083] To the blank solution, 5 mL of the evaluation sample and 2 mL of acetic acid-sodium acetate buffer solution (pH 5.6) were added.

[0084] The evaluation solution was prepared by adding 5 mL of the evaluation sample, 2 mL of acetic acid-sodium acetate buffer solution (pH 5.6), and 3 drops of potassium ferricyanide solution.

[0085] If the colors of both solutions are the same, the complex suspension contains Fe. 2+ is determined to not exist.

[0086] (b) Detection of chloride ion concentration Equipment and reagents: SSWY-810 rapid measurement instrument for chloride ion content and standard solutions (0.005 mol / L and 0.0005 mol / L NaCl aqueous solutions). The chloride ion electrode and glass electrode were calibrated before the test. The chloride ion concentration was indicated by the electrode.

[0087] (c) Measurement of the reaction rate T75 for ascorbic acid reagent: 1. As a dilute solution, 0.9% sodium chloride solution. 2. Vitamin C (ascorbic acid) stock solution: 8.8 g of vitamin C was mixed with water to prepare 50 mL of stock solution. 3. Iron hydroxide sucrose complex stock solution: 15 mL of the iron hydroxide carbohydrate complex suspension from one of Examples 1-3 above was diluted to 50 mL with water.

[0088] method: All of the above solutions were maintained at 37° C. Test solutions included 20 mL of NaCl solution, 4 mL of vitamin C stock solution, and 1 mL of complex stock solution.

[0089] The iron released from the complex was measured by UV-vis spectrophotometer at 450 nm.

[0090] The iron content was calculated as follows: 100×[A(t)-A(n) / A(0)-A(n)] where A(t) is the absorbance at time interval t minutes, A(n) is the background absorbance, and A(0) is the absorbance at time 0 (initial).

[0091] The results are shown in Table 1 below.

[0092] [Table 1]

[0093] evaluation Four samples, stability samples 1-4, were prepared and investigated for stability for up to 3 months.

[0094] Stability Sample 1 contained 5 mL of iron hydroxide sucrose complex 3 in a sealed glass bottle, with the pH of the complex adjusted to 10.8 using HCl solution. The sample was stored at 40°C.

[0095] Stability Sample 2 contained the same complex as Stability Sample 1, except that it was sterilized by autoclaving before storage at 40°C.

[0096] Stability Sample 3 contained 5 mL of iron hydroxide sucrose complex 3 in a sealed glass bottle, where the pH of the complex had been adjusted to 7 using HCl solution. The sample was stored at 40°C.

[0097] Stability Sample 4 contained the same complex as Stability Sample 3, except that it was sterilized by autoclaving before storage at 40°C.

[0098] At the end of each month, the molecular weight was analyzed and the results are shown in Table 2 below.

[0099] [Table 2]

[0100] The results showed that the molecular weight remained almost unchanged after 3 months of storage at 40°C, indicating that the iron hydroxide sucrose complex is stable and can be sterilized at high temperature under high or neutral pH conditions.

[0101] Examples 4 to 8: Iron Hydroxide Carbohydrate Complexes 4 to 8 The complex was prepared by the following steps: (1) diluting the purified polynuclear iron hydroxide suspension of Example 1 with an equal amount of water; (2) mixing the diluted suspension with a carbohydrate to obtain a carbohydrate mixture; (3) adjusting the pH value of the carbohydrate mixture to 10 using 20% sodium hydroxide solution; and (4) heating the pH-adjusted carbohydrate mixture at 85°C for 1 hour to obtain the iron hydroxide carbohydrate complex as the product.

[0102] In Example 4, iron hydroxide carbohydrate complex 4, i.e., iron hydroxide erythritol complex, was obtained using erythritol as the carbohydrate in a ratio of iron:erythritol=45:10.5.

[0103] In Example 5, iron hydroxide carbohydrate complex 5, ie, iron hydroxide maltodextrin complex, was obtained using maltodextrin DE30-35 as the carbohydrate in a ratio of iron:maltodextrin DE30-35=30:50.

[0104] In Example 6, iron hydroxide carbohydrate complex 6, i.e., iron hydroxide maltodextrin glucose complex, was obtained using maltodextrin DE30-35 and glucose as carbohydrates (maltodextrin DE30-35:glucose=9:1) in a ratio of iron:carbohydrate=60:20.

[0105] In Example 7, iron hydroxide carbohydrate complex 7, i.e., iron hydroxide maltose complex, was obtained using maltose syrup (DE58.5:glucose=1:1) as the carbohydrate in a ratio of iron:maltose syrup=45:18.

[0106] In Example 8, iron hydroxide carbohydrate complex 8, i.e., iron hydroxide sorbitol complex, was obtained using sorbitol as the carbohydrate in a ratio of iron:sorbitol=45:12.

[0107] Figure 2 shows a structural diagram of the nanoparticles present in the iron hydroxide carbohydrate complex prepared by the method of the present invention. The nanoparticles are spherical iron carbohydrate colloids. In Figure 2, a represents the polynuclear iron hydroxide core, and b represents the carbohydrate shell that covers the iron core. The carbohydrate shell has the following functions: 1. stabilizing the iron hydroxide core, 2. maintaining the nanoparticles suspended in water, 3. controlling iron release, 4. reducing iron toxicity, and 5. improving the flavor of the iron hydroxide product, i.e., eliminating the undesirable metallic taste.

[0108] Examples 9 to 13: Iron hydroxide carbohydrate complex powders 9 to 13 Each of the iron hydroxide carbohydrate complexes 4-8 was spray dried to obtain the product in powder form.

[0109] Thus, Example 9 is the powder of the iron hydroxide erythritol complex of Example 4, Example 10 is the powder of the iron hydroxide maltodextrin complex of Example 5; Example 11 is the powder of the iron hydroxide maltodextrin glucose complex of Example 6, Example 12 is the powder of the iron hydroxide maltose complex of Example 7, Example 13 is a powder of the iron hydroxide sorbitol complex of Example 8.

[0110] evaluation Iron content and free Fe in iron hydroxide carbohydrate complex powders 9-13 3+ and Fe 2+The content, as well as chloride ion content, was assessed using the assay described above.

[0111] The results are shown in Table 3 below.

[0112] [Table 3]

[0113] Example 14: Ferric Citrate Complex Polynuclear iron hydroxide Polynuclear iron hydroxide was prepared using a three-step pH titration method similar to the procedure described in Example 1.

[0114] (1) Solution A (15,000 g) was prepared by dissolving 2,250 g of solid FeCl3·6H2O in water (15 wt%). In a separate container, solution B (13,500 g) was prepared by dissolving 1,350 g of Na2CO3 (10 wt%) in water. Solution B was added slowly to solution A at 25 °C with stirring until a pH value of 2.8 was reached. The resulting clear solution was allowed to equilibrate for 5 minutes or until all CO2 bubbles had been released.

[0115] (2) Solution B was added to the clear solution from step (1) with stirring at 25°C until the pH reached 3.8, during which time iron hydroxide precipitated. Vigorous stirring was required due to a significant increase in viscosity. The suspension was allowed to equilibrate for 8 minutes to obtain a crude iron hydroxide suspension.

[0116] (3) To the crude iron hydroxide suspension was added the remainder of Solution B with stirring at 25°C. Upon completion, the resulting crude polynuclear iron hydroxide suspension was allowed to equilibrate for 10 minutes. An equal volume of water was added for the next step.

[0117] (4) The crude polynuclear iron hydroxide suspension thus obtained was purified by centrifugation and repeatedly washed with water until the conductivity of an aliquot remained unchanged. A wet cake of purified polynuclear iron hydroxide was obtained by removing the water after centrifugation.

[0118] Ferric citrate Purified iron hydroxide (0.4 mol) was suspended in an equal volume of water and mixed with a solution of citric acid (0.14 mol) and sodium citrate (0.14 mol). The resulting mixture was heated at 55-65°C for 15-30 minutes. The cloudy mixture became a clear, deep red solution. Tyndall behavior was observed, indicating the formation of colloids, i.e., ferric citrate complex nanoparticles uniformly dispersed in water.

[0119] Optionally, the clear solution of ferric citrate complex was spray dried to obtain ferric citrate complex powder.

[0120] Water solubility The iron(III) citrate powder (1 g) thus obtained was dispersed in 1 mL of water. The suspension was a clear, deep red solution, indicating a solubility in water of at least 50% by weight. The density was approximately 1.4 g / mL.

[0121] The water solubilities of commercial solid ferric citrate products were investigated for comparison. Ferric citrate 1 was commercially available from Yuzon Biotechnology Co., Ltd. (Zhengzhou, China). Ferric citrate 2 was commercially available from KonTai Food Additive Company Co., Ltd. (Tianjin, China). Both commercial products (1 g) were dispersed in water (up to 100 mL). At a concentration of 1 wt%, neither product was completely dissolved, indicating a water solubility of less than 1 wt%.

[0122] The ferric citrate complex of the present invention exhibits high aqueous solubility, which translates into great bioavailability, making the complex suitable for high-strength liquid products.

[0123] pH stability The iron(III) citrate powder of the present invention (1 g) was dispersed in 1 mL of water to obtain a clear solution. The pH of the clear solution was adjusted to 7, 3.5, 2.5, or 1.5 using 1N HCl (aqueous solution). The solution remained clear at each pH value, indicating stability at pHs between 1.5 and 7.

[0124] molecular weight The molecular weight of the ferric citrate suspension thus obtained was analyzed using the GPC method described above. The weight-average molecular weight of the suspension was found to be approximately 35,000 to 45,000 daltons. A ferric citrate product with this molecular weight has ideal bioavailability and iron release rate.

[0125] thermal stability The ferric citrate suspension was heated at 90°C for 6 hours to confirm its thermal stability. No changes were observed in terms of appearance, solution clarity, or GPC profile, indicating that the ferric citrate product is thermally stable. This good thermal stability makes the product suitable for the preparation of sterile injectable products.

[0126] Stability after spray drying Two samples were compared to demonstrate whether spray drying altered the ferric citrate complex nanoparticles. The first sample was the ferric citrate suspension obtained by the procedure described above. The second sample was a ferric citrate suspension prepared by dissolving the spray-dried ferric citrate complex powder in water to the same concentration as the first sample. The two samples were identical in terms of appearance, solution clarity, and GPC profile. The results indicated that the ferric citrate complex solution of the present invention maintained its quality after spray drying, a process that is not suitable for many commercial ferric products due to reduced solubility. Instead, an organic solvent was used to precipitate the solid ferric product. See, for example, U.S. Patent No. 7,674,780.

[0127] Fe 3+ and Fe 2+ Free Fe in a freshly prepared ferric citrate complex suspension according to the procedure described above 3+ and Fe 2+ The presence or absence of free Fe was examined. 3+ or Fe 2+ The results showed that no ions were present.

[0128] Free Fe 3+ or Fe 2+ The ions are incompatible with many ingredients in pharmaceutical or nutritional formulations. Furthermore, these ions are responsible for an unpleasant metallic taste.

[0129] Fe 3+ or Fe 2+ The absence of ions makes the ferric citrate products of the present invention suitable for formulation into pharmaceutical or nutritional preparations.

[0130] Example 15: Ferric Pyrophosphate Citrate Complex The procedure described in Example 14 was followed, except that a citric acid (0.3 mol) and pyrophosphate (0.3 mol) solution was used instead of the citric acid / citrate solution to obtain the ferric pyrophosphate citrate complex.

[0131] Example 16: Ferric gluconate The procedure described in Example 14 was followed, except that a gluconate (0.4 mol) solution was used instead of the citric acid / citrate solution to obtain the ferric gluconate of the present invention.

[0132] Example 17: Flavor evaluation A powder of iron hydroxide maltodextrin glucose complex (Example 11) was dispersed in an equal amount of water to obtain a colloid. Water and flavoring agents were added to the colloid to obtain free Fe. 3+ and Fe 2+ Test samples containing 1%, 5%, and 10% iron were prepared to detect the aftertaste of iron. No undesirable metallic aftertaste was found to be present in the test samples.

[0133] Example 18: Treatment of iron deficiency anemia Powder of iron hydroxide maltodextrin glucose complex (Example 11) was formulated into an oral liquid formulation containing 22.5 mg of iron in 10 mL of colloidal solution (Fe=0.25 wt %). Five female patients were instructed to take the formulation orally daily on specific days (see Table 4 below). Blood samples were analyzed using a Mission Hemoglobin Analyzer to measure hemoglobin levels. The results are shown in Table 4.

[0134] [Table 4]

[0135] As shown in Table 4 above, there is a significant increase in hemoglobin concentration with each use after taking the iron hydroxide carbohydrate complex of the present invention.

[0136] Other embodiments All features disclosed herein can be combined in any combination. Each feature disclosed herein can be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is merely an example of a generic series of equivalent or similar features.

[0137] From the above description, those skilled in the art can easily ascertain the essential features of the present invention, and can make various changes and modifications to the present invention to adapt it to various uses and conditions without departing from the spirit and scope of the present invention. For example, complexes structurally similar to the complexes of the present invention can also be produced and screened for their effectiveness in treating iron deficiency anemia.

Claims

1. 1. A method for preparing an iron hydroxide product, said method comprising: adding a first base solution to a solution of a ferric salt to obtain a mixture A having a pH value of 2.7 to 2.8; adding a second base solution to mixture A to prepare a crude iron hydroxide suspension having a pH value of 2.8 to 3.8; adding a third base solution to adjust the pH of the crude iron hydroxide suspension to 5 to 9, and then purifying and concentrating the crude iron hydroxide suspension to obtain a purified polynuclear iron hydroxide suspension containing polynuclear iron hydroxide; A method comprising:

2. 10. The method of claim 1, wherein Mixture A is equilibrated for 1 minute to 15 minutes before adding the second base, and the coarse iron hydroxide suspension is equilibrated for 2 minutes to 60 minutes before adding the third base.

3. 3. The method of claim 1 or 2, wherein each of the first base solution, the second base solution, and the third base solution is independently added at a temperature of from 15°C to 50°C.

4. 4. The method of claim 1, wherein the crude iron hydroxide suspension is purified by washing with water and concentrated by removing water to an iron hydroxide concentration of 3% to 16% by weight, and the purified iron hydroxide suspension has a chlorine content of less than 1%.

5. The first base solution, the second base solution, and the third base solution each independently comprise NaHCO ３ , Na ２ CO ３ , (NH ４ ) ２ CO ３ , and K ２ CO ３ The method according to any one of claims 1 to 4, wherein the aqueous solution is an aqueous solution of a carbonate selected from the group consisting of:

6. Each of the first base solution, the second base solution, and the third base solution contains Na having a mass percentage of 1% to 25%. ２ CO ３ 6. The method of claim 5, wherein the aqueous solution is

7. The ferric salt is Fe ２ (SO ４ ) ３ , Fe(NO ３ ) ３ , and FeCl ３ The method of any one of claims 1 to 6, wherein the compound is selected from the group consisting of:

8. The ferric salt is FeCl having a mass fraction of 5% to 60% in solution. ３ The method according to any one of claims 1 to 7, wherein

9. mixing the purified polynuclear iron hydroxide suspension with a carbohydrate to obtain a carbohydrate mixture; adjusting the pH value of the carbohydrate mixture to between 7.5 and 13, or between 10 and 13.5; heating the pH adjusted carbohydrate mixture to a temperature of 60°C to 125°C to produce an iron hydroxide carbohydrate complex suspension; The iron to carbohydrate mass ratio is (1-1100):100; the iron hydroxide product is the iron hydroxide carbohydrate complex; The method according to any one of claims 1 to 8.

10. 10. The method of claim 9, wherein the carbohydrate is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, polysaccharides, hydrolyzed polysaccharides, and any combination thereof.

11. The pH value of the carbohydrate mixture is ４ 11. The method according to claim 9 or 10, wherein the fourth base is adjusted to be a hydroxide solution selected from the group consisting of OH solution, KOH solution, and NaOH solution, and the hydroxide solution has a mass proportion of 5% to 50%.

12. 12. The method according to any one of claims 9 to 11, wherein the pH value of the carbohydrate mixture is adjusted to between 10 and 13.5 and the pH adjusted carbohydrate mixture is heated at between 80°C and 125°C for between 1 hour and 50 hours.

13. The carbohydrate is sucrose, and Fe ３＋ The method according to any one of claims 9 to 12, wherein the mass ratio of sucrose to corn starch is 1: (10 to 20).

14. 14. The method according to any one of claims 9 to 13, wherein the pH value of the iron hydroxide carbohydrate complex suspension is adjusted to 5.5 to 11.1 using a pH adjuster.

15. 15. The method of claim 14, wherein the pH adjuster is HCl, NaOH, citric acid, oxalic acid, fumaric acid, tartaric acid, succinic acid, malic acid, ascorbic acid, phosphoric acid, pyrophosphate, or glycolic acid.

16. 16. The method of any one of claims 9 to 15, further comprising the step of drying the iron hydroxide carbohydrate complex suspension.

17. 17. The method of any one of claims 9 to 16, wherein the iron hydroxide carbohydrate complex has a weight average molecular weight of 30,000 to 60,000 daltons, a reaction rate T75 with ascorbic acid of 35 minutes or less, and is free of free ferric ions.

18. 12. The method according to any one of claims 9 to 11, wherein the pH value of the carbohydrate mixture is adjusted to between 7.5 and 13 and the pH adjusted carbohydrate mixture is heated for between 0.2 hours and 30 hours.

19. 19. The method of claim 18, wherein the pH value of the carbohydrate mixture is adjusted to 9-12.5, and the pH-adjusted carbohydrate mixture is heated at a temperature of 65°C to 121°C for 0.2 hours to 30 hours, and the mass ratio of iron to carbohydrate is (1-264):

24.

20. 20. The method of any one of claims 9 to 11, 18 and 19, wherein the iron hydroxide carbohydrate complex having a solubility in water of 20% by weight or more contains 10% to 47% iron and less than 1% chloride ions by dry weight.

21. 21. The method of any one of claims 9-11 and 18-20, further comprising formulating the iron hydroxide carbohydrate complex into a drop, oral liquid, suspension, injectable solution, powder, capsule, tablet, or lozenge for treating iron deficiency anemia in a human or animal.

22. mixing the purified polynuclear iron hydroxide suspension with citric acid, a citrate salt, or a combination thereof to obtain a citrate mixture; heating the citrate mixture for 2 to 180 minutes at a temperature of 45 to 95°C to produce a ferric citrate suspension containing an iron hydroxide citrate complex; wherein the molar ratio of iron to citrate is 1:(0.3-5); 9. The method of any one of claims 1 to 8, wherein the iron hydroxide product is an iron hydroxide citrate complex.

23. 23. The method of claim 22, wherein the iron hydroxide citrate complex having a solubility in water of 20% by weight or greater contains 5% to 35% iron by dry weight and is free of free ferric ion.

24. 24. The method of claim 22 or 23, further comprising drying the ferric citrate suspension to form a dry iron hydroxide citrate complex.

25. 25. The method of claim 24, further comprising formulating the dry iron hydroxide citrate complex into a drop, oral liquid, suspension, injectable solution, powder, capsule, tablet, or lozenge for treating iron deficiency anemia in a human or animal.

26. mixing the purified polynuclear iron hydroxide suspension with a solution containing (i) citric acid or a citrate, and (ii) pyrophosphoric acid or a pyrophosphate to obtain a pyrophosphate mixture; heating the pyrophosphate mixture at a temperature of 55°C to 65°C for 5 minutes to 10 hours to produce a ferric citrate pyrophosphate suspension; wherein the molar ratio of iron:citrate:pyrophosphate is 1:(0.3-3):(0.3-3); 9. The method of any one of claims 1 to 8, wherein the iron hydroxide product is an iron hydroxide citrate pyrophosphate complex.

27. 27. The method of claim 26, wherein the iron hydroxide citrate pyrophosphate complex, having a solubility in water of 20% by weight or greater, contains 3% to 35% iron by dry weight.

28. mixing the purified polynuclear iron hydroxide suspension with a carboxylated carbohydrate, or a mixture thereof, to obtain a carboxylated carbohydrate mixture; heating the carboxylated carbohydrate mixture at a temperature of 65°C to 125°C for 5 minutes to 10 hours to produce a ferric carboxylated carbohydrate suspension; wherein the molar ratio of iron to said carboxylated carbohydrate is 1:(0.3-5), and said iron hydroxide product is an iron hydroxide carboxylated carbohydrate. The method according to any one of claims 1 to 8.

29. 29. The method of claim 28, wherein the carboxylated carbohydrate is gluconate.

30. mixing the purified polynuclear iron hydroxide suspension with a polyvalent anion to obtain a polyvalent anion mixture; adjusting the pH value of the polyvalent anion mixture to 2-13; and heating the pH-adjusted polyvalent anion mixture to a temperature of 40°C-125°C to prepare a nano-ferric complex suspension; The mass ratio of iron to the polyvalent anion is (1 to 1100):100; the iron hydroxide product is the nano-ferric complex; The method according to any one of claims 1 to 8.

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