Use of lanthanum oxyhydroxide in preparation of drug for treating hyperphosphatemia or disease associated with hyperphosphatemia

Abstract

Provided is the use of lanthanum oxyhydroxide in the preparation of a drug for treating hyperphosphatemia or a disease associated with hyperphosphatemia. The lanthanum oxyhydroxide is used for the preparation of a drug for treating hyperphosphatemia or a disease associated with hyperphosphatemia, wherein lanthanum oxyhydroxide has a relatively high lanthanum content of up to 80.8%, and accordingly, a relatively small dosage or formulation specification is required to bind the same amount of phosphate in the blood of a patient having hyperphosphatemia, which is beneficial for improving patient compliance, and same also exhibits a good phosphorus-lowering effect.

Description

Application of basic lanthanum oxide in the preparation of drugs for treating hyperphosphatemia or diseases related to hyperphosphatemia

[0001] This application claims priority to Chinese Patent Application No. CN202510192377.X, filed on April 11, 2025, entitled "Use of basic lanthanum oxide in the preparation of a medicament for treating hyperphosphatemia or diseases related to hyperphosphatemia", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to the field of pharmaceutical technology, and in particular to the use of basic lanthanum oxide in the preparation of medicaments for treating hyperphosphatemia or diseases related to hyperphosphatemia. Background Technology

[0003] Chronic kidney disease is a prevalent public health problem worldwide. One of its major complications is hyperphosphatemia, caused by the kidneys' inability to excrete phosphate from the body, leading to elevated blood phosphate levels. Symptoms of hyperphosphatemia primarily include blood phosphate levels exceeding normal levels, and it may be associated with secondary hyperparathyroidism, metabolic bone disease, soft tissue calcification, and cardiovascular calcification.

[0004] Currently, the main treatments for hyperphosphatemia include controlling phosphorus intake through diet, dialysis to remove phosphorus, the use of phosphate binders, and parathyroidectomy when necessary. Among these, 90-95% of patients with end-stage renal disease treat hyperphosphatemia by taking phosphate binders to reduce intestinal phosphorus absorption.

[0005] Phosphate binders are mainly divided into two categories: traditional aluminum- or calcium-containing phosphate binders and non-aluminum, non-calcium phosphate binders. Aluminum-containing phosphate binders, such as aluminum hydroxide and aluminum carbonate, can cause aluminum poisoning with long-term use, leading to microcytic anemia, osteomalacia, and Alzheimer's disease. Calcium-containing phosphate binders, such as calcium carbonate and calcium acetate, can increase calcium absorption in the intestines with long-term use, causing hypercalcemia and leading to calcification of the heart and blood vessels. Therefore, the ideal binders for treating hyperphosphatemia are non-aluminum, non-calcium phosphate binders.

[0006] The main non-aluminum, non-calcium phosphate binders currently available on the market are lanthanum carbonate chewable tablets. Anhydrous lanthanum carbonate contains 60.7% lanthanum, while its hydrated form contains less than 60.7%. The large dosage form leads to poor patient compliance. Patients may experience gastrointestinal adverse reactions such as nausea and vomiting after taking lanthanum carbonate. This is the main shortcoming of lanthanum carbonate as a phosphate binder in clinical practice, resulting in poor patient compliance and some patients failing to achieve their target phosphorus levels. Summary of the Invention

[0007] The purpose of this application is to provide the use of basic lanthanum oxide in the preparation of drugs for treating hyperphosphatemia or diseases related to hyperphosphatemia. This application uses basic lanthanum oxide to prepare drugs for treating hyperphosphatemia or diseases related to hyperphosphatemia, which can reduce the dosage form, improve patient compliance, and has a good phosphorus-lowering effect.

[0008] To achieve the above-mentioned objectives, this application provides the following technical solution:

[0009] This application provides the use of basic lanthanum oxide in the preparation of medicaments for treating hyperphosphatemia or diseases related to hyperphosphatemia.

[0010] This invention provides the use of one or more of the following in the preparation of medicaments for treating hyperphosphatemia or diseases related to hyperphosphatemia: basic lanthanum oxide containing lanthanum isotopes and / or oxygen isotopes, basic lanthanum oxide solvates, and complex salts containing basic lanthanum oxide.

[0011] Preferably, the diseases associated with hyperphosphatemia include chronic kidney disease, renal failure, secondary hyperparathyroidism, metabolic skeletal disease, soft tissue calcification, or cardiovascular calcification.

[0012] Preferably, the basic lanthanum oxide is in powder form.

[0013] Preferably, the basic lanthanum oxide comprises a monocrystalline form or an amorphous form.

[0014] Preferably, the surface of the basic lanthanum oxide is smooth or rough.

[0015] Preferably, the basic lanthanum oxide has a porous structure.

[0016] Preferably, the method for preparing the basic lanthanum oxide includes any one of the following:

[0017] Method 1: Calcining lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide;

[0018] Method 2: Mix an alkaline reagent, water, and lanthanum salt and / or lanthanum hydrate to carry out a metathesis reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; calcine the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide.

[0019] Method 3: Mix the dispersant, alkaline reagent, water, and lanthanum salt and / or lanthanum hydrate, and carry out a metathesis reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; calcine the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide;

[0020] Method 4: Lanthanum oxide is mixed with water to carry out a chemical reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; the lanthanum hydroxide and / or lanthanum hydroxide hydrate is then calcined to obtain the basic lanthanum oxide.

[0021] Method 5: Lanthanum oxide, a dispersant, and water are mixed to carry out a chemical reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; the lanthanum hydroxide and / or lanthanum hydroxide hydrate are then calcined to obtain the basic lanthanum oxide.

[0022] Preferably, the calcination temperature in methods one, two, three, four, and five is independently 200–800°C, and the calcination time is independently 1–72 h.

[0023] Preferably, the alkaline reagent in methods two and three independently includes alkali metal hydroxide or ammonia; the dispersant in methods three and five independently includes polyethylene glycol, surfactant or ionic liquid.

[0024] Preferably, the concentration of the ammonia water is 0.1 to 15.0 M; the ratio of the amount of lanthanum salt and / or lanthanum salt hydrate to ammonia water is 1 g: 0.5 to 10 mL.

[0025] Preferably, the alkali metal hydroxide includes potassium hydroxide, sodium hydroxide, or lithium hydroxide; the mass ratio of the lanthanum salt and / or lanthanum salt hydrate to the alkali metal hydroxide is 1:0.2 to 5.

[0026] Preferably, in methods three and five, lanthanum salt and / or lanthanum salt hydrate are used as lanthanum raw materials, and the mass of the dispersant is 0.5 to 10.0% of the total mass of the lanthanum raw materials.

[0027] Preferably, the polyethylene glycol is PEG400, PEG600 or PEG20000.

[0028] Preferably, the surfactant is polyvinylpyrrolidone or hexadecyltrimethylammonium bromide.

[0029] Preferably, the ionic liquid is an N-methyl-N-benzylmorpholine ionic liquid.

[0030] Preferably, in methods two and three, the temperature of the metathesis reaction is independently 0–200°C, the pressure is independently 0.1–2.0 MPa, and the time is independently 1–24 h.

[0031] Preferably, in methods four and five, the ratio of lanthanum oxide to water is independently 1g:10-30mL.

[0032] Preferably, the temperature of the combination reaction in methods four and five is 0–200°C, the pressure is 0.1–2.0 MPa, and the time is 1–24 h.

[0033] This application provides a medicament for treating hyperphosphatemia or diseases related to hyperphosphatemia, comprising an active ingredient and pharmaceutically acceptable excipients; said active ingredient is basic lanthanum oxide.

[0034] This application provides a medicament for treating hyperphosphatemia or diseases related to hyperphosphatemia, comprising an active ingredient and pharmaceutically acceptable excipients; said active ingredient comprising one or more of the following components: basic lanthanum oxide solvate; basic lanthanum oxide containing lanthanum isotopes and / or oxygen isotopes; and a complex salt containing basic lanthanum oxide.

[0035] Preferably, the content of the active ingredient in the drug is 0.1 to 99.9 wt%.

[0036] Preferably, the pharmaceutically acceptable excipients include pharmaceutical carriers and / or diluents.

[0037] Preferably, the dosage form of the drug includes granules, tablets, capsules, chewable tablets, powders, suspensions, or dry suspensions.

[0038] The present invention provides a method for treating hyperphosphatemia or diseases related to hyperphosphatemia, comprising administering an effective amount of an active ingredient, said active ingredient being basic lanthanum oxide, to a patient suffering from hyperphosphatemia or diseases related to hyperphosphatemia.

[0039] This invention provides a method for treating hyperphosphatemia or hyperphosphatemia-related diseases, comprising administering an effective amount of an active ingredient to a patient suffering from hyperphosphatemia or hyperphosphatemia-related diseases, said active ingredient comprising one or more of the following components: basic lanthanum oxide solvate; basic lanthanum oxide containing lanthanum isotopes and / or oxygen isotopes; and a complex salt containing basic lanthanum oxide.

[0040] This application discloses the use of basic lanthanum oxide in the preparation of medicaments for treating hyperphosphatemia or hyperphosphatemia-related diseases. This application utilizes basic lanthanum oxide to prepare medicaments for treating hyperphosphatemia or hyperphosphatemia-related diseases. The basic lanthanum oxide has a higher lanthanum content, reaching 80.8%. Developing it for the preparation of medicaments for treating hyperphosphatemia or hyperphosphatemia-related diseases requires a smaller dosage or formulation size for the same amount of phosphate, which is beneficial for improving patient compliance and exhibiting better phosphorus-lowering effects. Test results from this application show that basic lanthanum oxide has a higher lanthanum release and lanthanum-phosphorus binding effect than lanthanum carbonate in in vitro experiments. Furthermore, in vivo animal experiments show that basic lanthanum oxide can effectively reduce blood phosphorus concentration, indicating that basic lanthanum oxide has good development potential and value as a medicament for treating hyperphosphatemia and hyperphosphatemia-related diseases. Attached Figure Description

[0041] Figure 1 shows the dissolution curves of basic lanthanum oxide and lanthanum carbonate in a hydrochloric acid solution with pH = 1.2.

[0042] Figure 2 shows the dissolution curves of basic lanthanum oxide and lanthanum carbonate in an acetate buffer solution with a pH of 3.0.

[0043] Figure 3 shows the dissolution curves of basic lanthanum oxide and lanthanum carbonate in an acetate buffer solution with a pH of 5.0. Detailed Implementation

[0044] This application provides the use of basic lanthanum oxide in the preparation of medicaments for treating hyperphosphatemia or diseases related to hyperphosphatemia.

[0045] This invention provides the use of one or more of the following in the preparation of medicaments for treating hyperphosphatemia or diseases related to hyperphosphatemia: basic lanthanum oxide containing lanthanum isotopes and / or oxygen isotopes, basic lanthanum oxide solvates, and complex salts containing basic lanthanum oxide.

[0046] Currently, the main commercially available drugs for treating hyperphosphatemia are lanthanum carbonate chewable tablets. Anhydrous lanthanum carbonate contains 60.7% lanthanum, while its hydrated form contains less than 60.7%. The large dosage form results in poor patient compliance, and patients often experience gastrointestinal adverse reactions such as nausea and vomiting after taking lanthanum carbonate. This application utilizes basic lanthanum oxide to prepare a drug for treating hyperphosphatemia or related diseases. Basic lanthanum oxide has a higher lanthanum content, reaching 80.8%. Developing it into a drug for treating hyperphosphatemia or related diseases, combined with the requirement for a smaller dosage or dosage form for the same amount of phosphate, will improve patient compliance. Detailed explanation follows.

[0047] As one embodiment of this application, the diseases associated with hyperphosphatemia may include chronic kidney disease, renal failure, secondary hyperparathyroidism, metabolic skeletal disease, soft tissue calcification, or cardiovascular calcification.

[0048] In one embodiment of this application, the basic lanthanum oxide can be in powder form; the basic lanthanum oxide can include a single crystal form or an amorphous form. In another embodiment of this application, the surface of the basic lanthanum oxide can be smooth or rough, and the basic lanthanum oxide can have a porous structure.

[0049] This application provides a method for preparing basic lanthanum oxide suitable for treating hyperphosphatemia or diseases related to hyperphosphatemia, which is described in detail below.

[0050] As one embodiment of this application, the method for preparing basic lanthanum oxide may include any of the following:

[0051] Method 1: Calcining lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide;

[0052] Method 2: Mix an alkaline reagent, water, and lanthanum salt and / or lanthanum hydrate to carry out a metathesis reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; calcine the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide.

[0053] Method 3: Mix the dispersant, alkaline reagent, water, and lanthanum salt and / or lanthanum hydrate, and carry out a metathesis reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; calcine the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide;

[0054] Method 4: Lanthanum oxide is mixed with water to carry out a chemical reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; the lanthanum hydroxide and / or lanthanum hydroxide hydrate is then calcined to obtain the basic lanthanum oxide.

[0055] Method 5: Lanthanum oxide, a dispersant, and water are mixed to carry out a chemical reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; the lanthanum hydroxide and / or lanthanum hydroxide hydrate are then calcined to obtain the basic lanthanum oxide.

[0056] The various preparation methods are described in detail below.

[0057] Method 1:

[0058] This application describes the calcination of lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide.

[0059] As one embodiment of this application, the lanthanum hydroxide and / or lanthanum hydroxide hydrate can be commercially available products known to those skilled in the art, or can be prepared using methods known to those skilled in the art.

[0060] As one embodiment of this application, the calcination temperature can be 200–800°C, more specifically 300–500°C, and can be 300°C, 330°C, 350°C, 380°C, 400°C, 420°C, 450°C, or 500°C; the calcination time can be 1–72 h, more specifically 4–48 h, and can be 4 h, 8 h, 12 h, 16 h, 18 h, 24 h, 36 h, or 48 h; the calcination can be carried out in a protective atmosphere, specifically using nitrogen or an inert gas (such as argon or helium) to provide the protective atmosphere.

[0061] Method 2:

[0062] This application involves mixing an alkaline reagent, water, and lanthanum salt and / or lanthanum hydrate to perform a metathesis reaction, yielding lanthanum hydroxide and / or lanthanum hydroxide hydrate; and calcining the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide.

[0063] In one embodiment of this application, the lanthanum salt may include one or more of lanthanum chloride, lanthanum nitrate, lanthanum sulfate, and lanthanum acetate, specifically lanthanum chloride, lanthanum nitrate, lanthanum sulfate, or lanthanum acetate. In another embodiment, the lanthanum salt may be a commercially available product known to those skilled in the art, or it may be prepared using methods known to those skilled in the art. For example, lanthanum oxide, an acid reagent, and water may be mixed and reacted to obtain a lanthanum salt solution, which can then be directly mixed with a base reagent to perform a metathesis reaction. The acid reagent may be specifically selected based on the desired type of lanthanum salt, for example, nitric acid.

[0064] In one embodiment of this application, the alkaline reagent may include alkali metal hydroxide or ammonia. In another embodiment, the concentration of the ammonia may be 0.1–15.0 M, specifically 0.1 M, 1 M, 5 M, 10 M, 11 M, 12 M, 13 M, 14 M, or 15 M; the ratio of the amount of lanthanum salt and / or lanthanum salt hydrate to ammonia may be 1 g: 0.5–10 mL, specifically 1 g: 0.6 mL, 1 g: 0.7 mL, 1 g: 3 mL, 1 g: 6 mL, or 1 g: 8 mL. As one embodiment of this application, the alkali metal hydroxide may include potassium hydroxide, sodium hydroxide, or lithium hydroxide; the concentration of the alkaline reagent in the system during the metathesis reaction can be 0.1–15.0 M, specifically 0.1 M, 0.5 M, 0.8 M, 1 M, 1.2 M, 1.5 M, 2 M, 5 M, 10 M, or 15 M; the mass ratio of the lanthanum salt and / or lanthanum salt hydrate to the alkali metal hydroxide can be 1:0.2–5, specifically 1:0.3, 1:0.5, 1:1, 1:3, or 1:5.

[0065] In one embodiment of this application, the temperature of the metathesis reaction can be 0–200°C, more specifically 20–150°C, and more specifically 25°C, 30°C, 50°C, 80°C, 100°C, or 120°C; the pressure can be 0.1–2.0 MPa, i.e., atmospheric pressure or high pressure, and more specifically 0.2 MPa, 0.5 MPa, or 1.0 MPa; the time can be 1–24 h, and more specifically 2 h, 4 h, 8 h, 12 h, or 16 h. In another embodiment of this application, the metathesis reaction may further include: solid-liquid separation of the lanthanum hydroxide colloidal solution obtained after the metathesis reaction, collecting the solid material and sequentially washing and drying it to obtain the lanthanum hydroxide and / or lanthanum hydroxide hydrate. In one embodiment of this application, the solid-liquid separation method can be filtration or centrifugation; the washing reagent can be water, specifically deionized water; the drying temperature can be 30–150°C, more specifically 80–120°C, specifically 100–110°C; the drying time can be 1–10 hours, more specifically 2–8 hours, specifically 3–5 hours. In another embodiment of this application, the calcination conditions can refer to Method 1 described above, and will not be repeated here.

[0066] Method 3:

[0067] This application involves mixing a dispersant, an alkaline reagent, water, and lanthanum salt and / or lanthanum hydrate to perform a metathesis reaction, yielding lanthanum hydroxide and / or lanthanum hydroxide hydrate; and calcining the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide.

[0068] In one embodiment of this application, the dispersant may include polyethylene glycol, a surfactant, or an ionic liquid; the polyethylene glycol may be PEG400, PEG600, or PEG20000; the surfactant may be polyvinylpyrrolidone or hexadecyltrimethylammonium bromide; the ionic liquid may be an N-methyl-N-benzylmorpholine ionic liquid; the mass of the dispersant may be 0.5–10.0 wt% of the total mass of the lanthanum raw material (i.e., lanthanum salt and / or lanthanum salt hydrate), specifically 0.5 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 8.0 wt%, or 10 wt%. In another embodiment of this application, the type and amount of the lanthanum salt and alkaline reagent, the metathesis reaction, and the calcination conditions can be referred to Method 2 above, and will not be repeated here.

[0069] Method 4:

[0070] This application involves mixing lanthanum oxide with water to undergo a chemical reaction, yielding lanthanum hydroxide and / or lanthanum hydroxide hydrate; and calcining the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide.

[0071] In one embodiment of this application, the water can be deionized water; the ratio of lanthanum oxide to water can be 1g:10-30mL, specifically 1g:10mL, 1g:15mL, 1g:20mL, 1g:25mL, or 1g:30mL. In another embodiment of this application, the temperature of the combination reaction can be 0-200℃, more specifically 20-150℃, specifically 40℃, 50℃, 60℃, 80℃, 90℃, 100℃, 110℃, or 130℃; the pressure can be 0.1-2.0MPa, i.e., atmospheric pressure or high pressure, without special limitation in this application; the time can be 1-24h, specifically 2h, 4h, 8h, 12h, or 16h. In one embodiment of this application, the chemical reaction may further include: allowing the lanthanum hydroxide colloidal solution obtained after the chemical reaction to stand and then separating the solid and liquid phases sequentially; collecting the solid material and then washing and drying it sequentially to obtain the lanthanum hydroxide and / or lanthanum hydroxide hydrate (specifically, lanthanum hydroxide and / or lanthanum hydroxide hydrate). In one embodiment of this application, the solid-liquid separation may be achieved through filtration or centrifugation; the washing reagent may be water, specifically deionized water; the drying temperature may be 30–150°C, further 80–120°C, specifically 100–110°C; the drying time may be 1–10 hours, further 2–8 hours, specifically 3–5 hours. In one embodiment of this application, the calcination conditions may refer to the above-described method one, and will not be repeated here.

[0072] Method 5:

[0073] This application involves mixing lanthanum oxide, a dispersant, and water to conduct a chemical reaction, yielding lanthanum hydroxide and / or lanthanum hydroxide hydrate (specifically, lanthanum hydroxide and / or lanthanum hydroxide hydrate); and calcining the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide.

[0074] In one embodiment of this application, the dispersant may include polyethylene glycol, a surfactant, or an ionic liquid; the polyethylene glycol may be PEG400, PEG600, or PEG20000; the surfactant may be polyvinylpyrrolidone or hexadecyltrimethylammonium bromide; the ionic liquid may be an N-methyl-N-benzylmorpholine ionic liquid; the mass of the dispersant may be 0.5–5.0 wt% of the mass of lanthanum oxide, specifically 0.5 wt%, 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, or 5.0 wt%. In another embodiment of this application, the ratio of lanthanum oxide to water, the chemical reaction, and the calcination conditions can be referred to Method 4 above, and will not be repeated here.

[0075] This invention provides a medicament for treating hyperphosphatemia or diseases related to hyperphosphatemia, comprising an active ingredient and pharmaceutically acceptable excipients; the active ingredient is basic lanthanum oxide.

[0076] This application provides a medicament for treating hyperphosphatemia or diseases related to hyperphosphatemia, comprising an active ingredient and pharmaceutically acceptable excipients; the active ingredient comprises one or more of the following components: basic lanthanum oxide solvate; basic lanthanum oxide containing lanthanum isotopes and / or oxygen isotopes; and a complex salt containing basic lanthanum oxide. As one embodiment of this application, the basic lanthanum oxide solvate may comprise basic lanthanum oxide hydrate and / or basic lanthanum oxide organic solvate.

[0077] In one embodiment of the present invention, the content of the active ingredient in the drug can be from 0.1 to 99.9 wt%. This application does not specifically limit the types of pharmaceutically acceptable excipients.

[0078] As one embodiment of this application, the dosage form of the drug may include granules, tablets, capsules, chewable tablets, powders, suspensions, or dry suspensions.

[0079] The present invention provides a method for treating hyperphosphatemia or diseases related to hyperphosphatemia, comprising administering an effective amount of an active ingredient, said active ingredient being basic lanthanum oxide, to a patient suffering from hyperphosphatemia or diseases related to hyperphosphatemia.

[0080] This invention provides a method for treating hyperphosphatemia or hyperphosphatemia-related diseases, comprising administering an effective amount of an active ingredient to a patient suffering from hyperphosphatemia or hyperphosphatemia-related diseases, said active ingredient comprising one or more of the following components: basic lanthanum oxide solvate; basic lanthanum oxide containing lanthanum isotopes and / or oxygen isotopes; and a complex salt containing basic lanthanum oxide.

[0081] This application provides a basic lanthanum oxide that meets pharmaceutical standards. Through in vitro lanthanum ion dissolution and release experiments, lanthanum-phosphorus binding experiments, and in vivo animal efficacy experiments, it has been demonstrated that the basic lanthanum oxide can be developed as a drug for the treatment of hyperphosphatemia and related diseases in humans. Furthermore, in in vivo animal efficacy studies, the basic lanthanum oxide provided in this application showed no adverse effects or toxicological reactions at therapeutic doses, indicating that the basic lanthanum oxide has good safety and good development potential and value.

[0082] The technical solutions of this application will be clearly and completely described below with reference to the embodiments therein. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this application without creative effort are within the scope of protection of this application.

[0083] Example 1

[0084] Weigh out 17.32 g of lanthanum nitrate hexahydrate, dissolve it in 50 mL of deionized water, and then add water to make up to 100 mL to obtain a lanthanum nitrate solution (0.4 mol / L).

[0085] Weigh out 4.8 g of sodium hydroxide, dissolve it in deionized water, cool it to room temperature, and then add water to make up to 100 mL to obtain a sodium hydroxide solution (1.2 mol / L).

[0086] PEG20000 (0.2598 g, added at 1.5 wt% of the mass of lanthanum nitrate hexahydrate) was added to the lanthanum nitrate solution, and the mixture was cooled to 10°C in an ice-water bath. Then, the sodium hydroxide solution was added dropwise. After the addition was complete, the mixture was stirred at room temperature (25°C) for 3 h. The mixture was filtered, and the filter cake was washed three times with deionized water and dried in an oven at 110°C for 3 h to obtain lanthanum hydroxide solid powder. 10 g of the lanthanum hydroxide solid powder was placed in a muffle furnace and calcined at 420°C for 8 h in a nitrogen atmosphere to obtain 9.10 g of basic lanthanum oxide.

[0087] Examples 2-11

[0088] Basic lanthanum oxide was prepared according to the method of Example 1, except that at least one of the raw materials, reaction conditions and calcination conditions was different, as detailed in Table 1. Cases not mentioned are the same as in Example 1.

[0089] Table 1. Conditions and results for the preparation of basic lanthanum oxide in Examples 1-11.

[0090] Example 12

[0091] Weigh 10.0 g of lanthanum oxide, add 200 mL of deionized water, heat to reflux temperature (100 °C) and stir for 12 h, then allow to cool naturally, stand, and filter. Wash the filter cake three times with deionized water and dry it in an oven at 110 °C for 3 h to obtain lanthanum hydroxide solid powder. Take 10 g of the lanthanum hydroxide solid powder and place it in a muffle furnace. Calcine it at 450 °C for 8 h in a nitrogen atmosphere to obtain 9.10 g of basic lanthanum oxide.

[0092] Example 13

[0093] The procedure was followed as in Example 12, except that the reaction temperature was 50°C, and 9.08 g of basic lanthanum oxide was finally obtained.

[0094] Example 14

[0095] Weigh 10.0 g of lanthanum oxide, add 200 mL of deionized water and 0.15 g of PEG20000, heat to reflux temperature (100 °C) and stir for 12 h, then cool naturally, let stand, filter, wash the filter cake three times with deionized water and dry in an oven at 110 °C for 3 h to obtain lanthanum hydroxide solid powder; take 10 g of the lanthanum hydroxide solid powder and put it into a muffle furnace, calcine at 450 °C for 24 h in a nitrogen atmosphere to obtain 9.13 g of basic lanthanum oxide.

[0096] Example 15

[0097] Weigh 178g of concentrated nitric acid with a concentration of 67wt%, add it to a beaker containing 500mL of deionized water, then dilute to 2L with deionized water, add 100g of lanthanum oxide in batches, stir at room temperature for 1h to obtain a clear lanthanum nitrate solution.

[0098] Measure 50 mL of 13M concentrated ammonia solution, add deionized water to make up to 650 mL, and obtain 1M ammonia solution.

[0099] 500 mL of the lanthanum nitrate solution was measured, and 325 mL of 1 M ammonia solution was added dropwise at room temperature. After the addition was complete, the mixture was heated to 80 °C and stirred for 2 h. The mixture was then cooled and filtered. The filter cake was washed three times with deionized water and dried in an oven at 110 °C for 3 h to obtain lanthanum hydroxide solid powder. 10 g of the lanthanum hydroxide solid powder was placed in a muffle furnace and calcined at 380 °C for 8 h in a nitrogen atmosphere to obtain 9.08 g of basic lanthanum oxide.

[0100] Example 16

[0101] Weigh 178g of concentrated nitric acid with a concentration of 67wt%, add it to a beaker containing 500mL of deionized water, then dilute to 2L with deionized water, add 100g of lanthanum oxide in batches, stir at room temperature for 1h to obtain a clear lanthanum nitrate solution.

[0102] Measure 50 mL of 13M concentrated ammonia solution, add deionized water to make up to 650 mL, and obtain 1M ammonia solution.

[0103] 500 mL of the lanthanum nitrate solution was measured, and 325 mL of 1 M ammonia solution was added dropwise at room temperature. After the addition was complete, 5.0 g of PEG20000 was added, and the mixture was heated to 80 °C and stirred for 2 h. After cooling and filtration, the filter cake was washed three times with deionized water and then dried in an oven at 110 °C for 3 h to obtain lanthanum hydroxide solid powder. 10 g of the lanthanum hydroxide solid powder was placed in a muffle furnace and calcined at 380 °C for 16 h in a nitrogen atmosphere to obtain 9.08 g of basic lanthanum oxide.

[0104] Example 17

[0105] Weigh 178g of concentrated nitric acid with a concentration of 67wt%, add it to a beaker containing 500mL of deionized water, then dilute to 2L with deionized water, add 100g of lanthanum oxide in batches, stir at room temperature for 1h to obtain a clear lanthanum nitrate solution.

[0106] Weigh 10g of sodium hydroxide, dissolve it in deionized water, cool it to room temperature, and then add water to make up to 250mL to obtain a 1M sodium hydroxide solution.

[0107] Measure 500 mL of the lanthanum nitrate solution and add 250 mL of the sodium hydroxide solution dropwise at room temperature. After the addition is complete, heat to 80 °C and stir for 3 h. Then cool and filter. Wash the filter cake three times with deionized water and place it in an oven at 110 °C for 3 h to obtain lanthanum hydroxide solid powder. Take 10 g of the lanthanum hydroxide solid powder and place it in a muffle furnace. Calcine it at 420 °C for 8 h in a nitrogen atmosphere to obtain 9.09 g of basic lanthanum oxide.

[0108] Example 18

[0109] Weigh 178g of concentrated nitric acid with a concentration of 67wt%, add it to a beaker containing 500mL of deionized water, then dilute to 2L with deionized water, add 100g of lanthanum oxide in batches, stir at room temperature for 1h to obtain a clear lanthanum nitrate solution.

[0110] Weigh 10g of sodium hydroxide, dissolve it in deionized water, cool it to room temperature, and then add water to make up to 250mL to obtain a 1M sodium hydroxide solution.

[0111] Measure 500 mL of the lanthanum nitrate solution and add 250 mL of the sodium hydroxide solution dropwise at room temperature. After the addition is complete, add 5.0 g of PEG20000, then heat to 80 °C and stir for 3 h. After cooling and filtration, wash the filter cake three times with deionized water and place it in an oven at 110 °C for 3 h to obtain lanthanum hydroxide solid powder. Take 10 g of the lanthanum hydroxide solid powder and place it in a muffle furnace. Calcine it at 420 °C for 8 h in a nitrogen atmosphere to obtain 9.10 g of basic lanthanum oxide.

[0112] The basic lanthanum oxides prepared in Examples 1-18 were subjected to XRD analysis, and the obtained XRD patterns were consistent with those of the standard cards.

[0113] Test Example: Leaching Experiments of Basic Lanthanum Oxide and Lanthanum Carbonate in Different Media

[0114] This test case examines the dissolution of lanthanum ions in solutions at different time points in different media, and compares the release rates of lanthanum ions in different media, as detailed below:

[0115] The testing media were: hydrochloric acid solution with pH = 1.2, acetate buffer solution with pH = 3.0, and acetate buffer solution with pH = 5.0.

[0116] Dissolution conditions: Temperature of each medium 37℃; 100 rpm; Volume: 900 mL; Sampling points: 0.5h, 1h, 1.5h, 2h, 3h (no replenishment).

[0117] Preparation process:

[0118] Basic lanthanum oxide: Take about 0.62g of this product (500mg of lanthanum element, specifically the basic lanthanum oxide prepared in Example 12, which was sieved through a 60-mesh sieve before the experiment), place it in a dissolution apparatus, and test it according to the dissolution conditions. Take samples at the specified time points, filter, and use the filtrate for analysis and detection.

[0119] Lanthanum carbonate: Take about 0.953g of this product (500mg of lanthanum, batch number: TSL-240622, sieved through 60 mesh before the experiment), place it in a dissolution apparatus, test according to the dissolution conditions, take samples at the specified time points, filter, and use the filtrate for analysis and detection.

[0120] Detection method: Dissolve 16.4g of anhydrous sodium acetate in 1000mL of water, adjust the pH to 6.2 with glacial acetic acid to obtain a 0.2mol / L acetate buffer solution; accurately measure 5mL of the above filtrate, place it in an Erlenmeyer flask, add 45mL of the 0.2mol / L acetate buffer solution and 5-6 drops of xylenol orange indicator solution, and titrate with 0.01mol / L disodium ethylenediaminetetraacetate titrant until the solution changes from pale purple to lemon yellow. Each 1mL of the disodium ethylenediaminetetraacetate titrant is equivalent to 1.39mg of La. Calculate the lanthanum content in the filtrate based on the amount of disodium ethylenediaminetetraacetate titrant used.

[0121] Figure 1 shows the dissolution curves of basic lanthanum oxide and lanthanum carbonate in hydrochloric acid solution with pH = 1.2; Figure 2 shows the dissolution curves of basic lanthanum oxide and lanthanum carbonate in acetate buffer solution with pH = 3.0; Figure 3 shows the dissolution curves of basic lanthanum oxide and lanthanum carbonate in acetate buffer solution with pH = 5.0; specific data are listed in Tables 2 to 4.

[0122] Table 2. Cumulative dissolution rates (%) of basic lanthanum oxide and lanthanum carbonate in hydrochloric acid solution with pH = 1.2.

[0123] Table 3. Cumulative dissolution rates (%) of basic lanthanum oxide and lanthanum carbonate in acetate buffer solution at pH 3.0

[0124] Table 4. Cumulative dissolution rates (%) of basic lanthanum oxide and lanthanum carbonate in acetate buffer solution at pH 5.0

[0125] The dissolution data and curves from different pH media show that the dissolution rates of basic lanthanum oxide and lanthanum carbonate are basically the same in dissolution media with pH = 1.2 and 3.0. However, when the pH increases to 5.0, the dissolution rate and cumulative dissolution of basic lanthanum oxide are significantly better than those of the control drug lanthanum carbonate, indicating that the dissolution of the control drug lanthanum carbonate is greatly affected by pH. Moreover, lanthanum-containing preparations are generally taken with food or after meals. The pH value of humans usually rises to 3-5 after meals. Therefore, it can be inferred that in human efficacy trials, when lanthanum carbonate and basic lanthanum oxide are taken after meals, the phosphorus-lowering rate and phosphorus-lowering amount of basic lanthanum oxide may be better than those of the control drug lanthanum carbonate. This suggests that basic lanthanum oxide preparations have better efficacy and potential value in lowering blood phosphorus, treating hyperphosphatemia and chronic kidney disease.

[0126] Pharmacodynamic evaluation of hyperphosphatemia induced by chronic renal failure in SD rats (experimental case)

[0127] By establishing a male SD rat model of chronic renal failure with hyperphosphatemia induced by 5 / 6 nephrectomy, with lanthanum carbonate as the positive control drug, the phosphate-lowering effect and renal function improvement of lanthanum oxide hydroxide at different doses on model animals were explored, and the pharmacodynamic characteristics of its treatment of hyperphosphatemia were comprehensively evaluated. The specific experiments are as follows:

[0128] Male SD rats, 6 weeks old, were purchased from SPF (Beijing) Biotechnology Co., Ltd.; the use license number: SYXK (Beijing) 2023-0004, and the certificate number: No. 110324251101765076.

[0129] Source of the test drug:

[0130] Lanthanum carbonate: batch number TSL-241253, Beijing Huaruidingxin Technology Co., Ltd.;

[0131] Lanthanum oxide hydroxide: batch number HRL1101-XXXXX, Beijing Huaruidingxin Technology Co., Ltd.;

[0132] Source of the solvent:

[0133] Sodium carboxymethyl cellulose (CMC-Na): batch number JS241201, Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.;

[0134] Corn oil: batch number 01033, Shandong Luhua Group Co., Ltd.

[0135] (1) Establishment of the animal model: Male SD rats were surgically removed the right whole kidney and about 2 / 3 of the left kidney (adrenal gland reserved), achieving a total reduction of about 5 / 6 in the volume of functional renal tissue. After 1 week of recovery after surgery, all animals were fed a high-phosphorus diet (phosphorus content 1.2 wt%). After continuously feeding the high-phosphorus diet for 7 weeks, with the significant increase in serum phosphorus, creatinine, and urea nitrogen levels as the core modeling indicators, the successfully modeled rats with similar serum phosphorus levels were selected, together with the sham-operated rats in the same period (only the renal capsule was separated, and no renal tissue was removed), as experimental animals. The selected model rats were randomly assigned to the drug administration groups, and the serum phosphorus, creatinine, and urea nitrogen data at this stage were used as the baseline values before drug administration.

[0136] (2) Preparation of the drug administration preparation: Weigh the required amount of the test drug, add a small amount of corn oil solution containing 1 wt% CMC-Na to the mortar, slowly grind for 10 min and then transfer, rinse the mortar with a small amount of corn oil solution containing 1 wt% CMC-Na multiple times, and make up the volume to the required volume, and vortex to mix evenly.

[0137] Note: The "XXXXX" in the batch number of Lanthanum oxide hydroxide in the translation is the original text's "25031401", which is a 7-digit tag that needs to be preserved exactly as-is according to the rules. Since it's not clear if it's a placeholder or an actual number, it's left in this form for now. If it has a specific meaning or needs to be translated in a certain way, more context would be required.(3) Grouping and administration: Serum phosphorus, creatinine, and blood urea nitrogen levels were used as the screening criteria for animal inclusion and as baselines. Inclusion animals were randomly divided into four groups: a model group, a lanthanum carbonate group (1000 mg / kg, lanthanum content approximately 500 mg / kg), a low-dose basic lanthanum oxide group (200 mg / kg, lanthanum content approximately 167 mg / kg), a medium-dose basic lanthanum oxide group (400 mg / kg, lanthanum content approximately 330 mg / kg), and a high-dose basic lanthanum oxide group (600 mg / kg, lanthanum content approximately 500 mg / kg), with 12 animals in each group. An additional 12 animals from a sham-operated group (without nephrectomy) served as the control group. The control and model groups were given a high-phosphorus diet and a daily oral gavage administration of the solvent. The lanthanum carbonate, low-dose, medium-dose, and high-dose basic lanthanum oxide groups were given the corresponding drug suspension (5 mL / kg) daily via oral gavage. Serum phosphorus levels were measured at weeks 4 and 6 after administration. After the 6th week of the experiment, the animals in each group were dissected, and 7 kidneys from each group were taken for HE staining to assess the extent of kidney damage.

[0138] Table 5 Grouping of experimental animals

[0139] (4) Experimental results: Table 6 shows that in the 6th week after administration, the serum phosphorus levels in the basic lanthanum oxide medium and high dose groups and the lanthanum carbonate group were significantly lower than those in the model group (p<0.05, p<0.001, p<0.01), indicating that both basic lanthanum oxide and lanthanum carbonate can significantly reduce the serum phosphorus level in model rats and show a mild alleviating trend in improving renal function (indicators of creatinine and blood urea nitrogen) and renal pathological damage in model rats.

[0140] Table 6. Statistical table of serum test data after 6 weeks of drug administration

[0141] Note: *p<0.05, **p<0.01 vs model group; #p<0.05, ###p<0.001 vs control group.

[0142] The above description is only a preferred embodiment of this application. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of this application, and these improvements and modifications should also be considered within the scope of protection of this application.

Claims

1. The use of a basic lanthanum oxide in the preparation of a drug for treating hyperphosphatemia or diseases related to hyperphosphatemia.

2. The use of one or more of the following in the preparation of drugs for treating hyperphosphatemia or diseases related to hyperphosphatemia: basic lanthanum oxide containing lanthanum isotopes and / or oxygen isotopes, basic lanthanum oxide solvates, and complex salts containing basic lanthanum oxide.

3. The application according to claim 1 or 2, characterized in that, The diseases associated with hyperphosphatemia include chronic kidney disease, renal failure, secondary hyperparathyroidism, metabolic bone disease, soft tissue calcification, or cardiovascular calcification.

4. The application according to claim 1 or 2, characterized in that, The basic lanthanum oxide is in powder form.

5. The application according to claim 1 or 2, characterized in that, The basic lanthanum oxide includes a single crystal form or an amorphous form.

6. The application according to claim 1 or 2, characterized in that, The surface of the basic lanthanum oxide is either smooth or rough.

7. The application according to claim 1 or 2, characterized in that, The basic lanthanum oxide has a porous structure.

8. The application according to claim 1, characterized in that, The preparation method of the basic lanthanum oxide includes any one of the following: Method 1: Calcining lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide; Method 2: Mix an alkaline reagent, water, and lanthanum salt and / or lanthanum hydrate to carry out a metathesis reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; calcine the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide. Method 3: Mix the dispersant, alkaline reagent, water, and lanthanum salt and / or lanthanum hydrate, and carry out a metathesis reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; calcine the lanthanum hydroxide and / or lanthanum hydroxide hydrate to obtain the basic lanthanum oxide; Method 4: Lanthanum oxide is mixed with water to carry out a chemical reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; the lanthanum hydroxide and / or lanthanum hydroxide hydrate is then calcined to obtain the basic lanthanum oxide. Method 5: Lanthanum oxide, a dispersant, and water are mixed to carry out a chemical reaction to obtain lanthanum hydroxide and / or lanthanum hydroxide hydrate; the lanthanum hydroxide and / or lanthanum hydroxide hydrate are then calcined to obtain the basic lanthanum oxide.

9. The application according to claim 8, characterized in that, In methods one, two, three, four, and five, the calcination temperature is independently 200–800℃, and the calcination time is independently 1–72h.

10. The application according to claim 8, characterized in that, In methods two and three, the alkaline reagents independently include alkali metal hydroxides or ammonia; in methods three and five, the dispersants independently include polyethylene glycol, surfactants, or ionic liquids.

11. The application according to claim 10, characterized in that, The concentration of the ammonia water is 0.1–15.0 M; the ratio of the amount of lanthanum salt and / or lanthanum salt hydrate to ammonia water is 1 g: 0.5–10 mL.

12. The application according to claim 10, characterized in that, The alkali metal hydroxide includes potassium hydroxide, sodium hydroxide, or lithium hydroxide; the mass ratio of the lanthanum salt and / or lanthanum salt hydrate to the alkali metal hydroxide is 1:0.2 to 5.

13. The application according to claim 10, characterized in that, In methods three and five, lanthanum salt and / or lanthanum salt hydrate are used as lanthanum raw materials, and the mass of the dispersant is 0.5 to 10.0% of the total mass of the lanthanum raw materials.

14. The application according to claim 10 or 13, characterized in that, The polyethylene glycol is PEG400, PEG600 or PEG20000.

15. The application according to claim 10 or 13, characterized in that, The surfactant is polyvinylpyrrolidone or hexadecyltrimethylammonium bromide.

16. The application according to claim 10 or 13, characterized in that, The ionic liquid is an N-methyl-N-benzylmorpholine ionic liquid.

17. The application according to claim 8, characterized in that, In Method 2 and Method 3, the temperature of the metathesis reaction is independently 0–200℃, the pressure is independently 0.1–2.0 MPa, and the time is independently 1–24 h.

18. The application according to claim 8, characterized in that, In methods four and five, the ratio of lanthanum oxide to water is independently 1g:10-30mL.

19. The application according to claim 8, characterized in that, In methods four and five, the temperature of the chemical reaction is 0–200℃, the pressure is 0.1–2.0 MPa, and the time is 1–24 h.

20. A medicament for treating hyperphosphatemia or diseases related to hyperphosphatemia, comprising an active ingredient and pharmaceutically acceptable excipients; said active ingredient being basic lanthanum oxide.

21. A medicament for treating hyperphosphatemia or diseases related to hyperphosphatemia, comprising an active ingredient and pharmaceutically acceptable excipients; said active ingredient comprising one or more of the following components: basic lanthanum oxide solvate; basic lanthanum oxide containing lanthanum isotopes and / or oxygen isotopes; and a complex salt containing basic lanthanum oxide.

22. The medicament according to claim 20 or 21, characterized in that, The active ingredient content in the drug is 0.1–99.9 wt%.

23. The medicament according to claim 20 or 21, characterized in that, Pharmaceutically acceptable excipients include pharmaceutical carriers and / or diluents.

24. The medicament according to claim 20 or 21, characterized in that, The dosage forms of the drug include granules, tablets, capsules, chewable tablets, powders, suspensions, or dry suspensions.

25. A method of treating hyperphosphatemia or a disease associated with hyperphosphatemia, comprising administering to a patient suffering from hyperphosphatemia or a disease associated with hyperphosphatemia an effective amount of an active ingredient, said active ingredient being basic lanthanum oxide.

26. A method of treating hyperphosphatemia or a disease associated with hyperphosphatemia, comprising administering to a patient suffering from hyperphosphatemia or a disease associated with hyperphosphatemia an effective amount of an active ingredient, said active ingredient comprising one or more of the following components: basic lanthanum oxide solvate; basic lanthanum oxide containing lanthanum isotopes and / or oxygen isotopes; and a complex salt containing basic lanthanum oxide.

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