Dry suspension comprising poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt and preparation method therefor

Abstract

The present invention relates to a dry suspension comprising poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, a suspending agent, and silicon dioxide or a solid powder flavor, and a preparation method therefor; the present invention further relates to the use of the dry suspension in the treatment of hyperkalemia.

Description

Dry suspension comprising poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt and method of making the same

[0001] This application claims the benefit of PCT Application No. PCT / CN2024 / 118869, filed September 13, 2024, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] The present application relates to the field of pharmaceutical formulations. More specifically, the present application relates to a dry suspension comprising poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt and a method of making the same. BACKGROUND

[0003] Potassium ion (K + ) is one of the most abundant cations in the human body, and plays an important role in maintaining cell metabolism, maintaining cell resting membrane potential, regulating osmotic pressure inside and outside the cell, and regulating acid-base balance. Under physiological conditions, the body maintains potassium homeostasis by balancing potassium intake and excretion, and regulating the distribution of potassium inside and outside the cell. About 98% of potassium is distributed inside the cell, and 2% is distributed outside the cell. The main source of potassium in the body is the intake of potassium from food. Adults need to intake about 3-4 g of potassium per day. The kidney is the main organ for potassium excretion, about 90-95% of which is excreted by the kidney, and the rest is mainly excreted by the colon. When the kidney function is not sufficient, the amount of potassium excreted by the colon increases, and in patients with end-stage renal disease, the amount of potassium excreted by the stool is three times that of people with normal kidney function.

[0004] The normal concentration of serum potassium ions is 3.5-5.0 mmol / L. Serum potassium concentration > 5.0 mmol / L is diagnosed as hyperkalemia. Serum potassium levels in the range of 5.0 mmol / L to 6.0 mmol / L are mild hyperkalemia, usually not life-threatening. However, moderate to severe hyperkalemia (serum potassium greater than about 6.1 mmol / L) can lead to serious consequences, arrhythmia and abnormal ECG waveform are characteristics of hyperkalemia. When serum potassium levels rise to about 9 mmol / L or higher, symptoms such as atrioventricular dissociation, ventricular tachycardia or ventricular fibrillation can occur. Hyperkalemia is divided into acute hyperkalemia and chronic hyperkalemia. A large-scale epidemiological study in China showed that among nearly 3 million outpatients with blood potassium examination records, the prevalence of hyperkalemia was 3.86%, among which the prevalence of hyperkalemia in patients with chronic kidney disease (CKD) was as high as 22.89%, and the proportion of hyperkalemia patients in the outpatient population of heart failure and diabetes was as high as 12.54% and 7.11% respectively (Bian J M et al. “Epidemiological study on the distribution and diagnosis of hyperkalemia in outpatients in China”, China Blood Purification, 2020 Nov, 19(11):726-729,746). A meta-analysis showed that the prevalence of hyperkalemia in the general outpatient population was 1.3%, but in non-dialysis CKD and dialysis-dependent CKD patients, it was as high as 7.5% and 35% respectively (Humphrey T et.al. “How common is hyperkalaemia?A systematic review and meta-analysis of the prevalence and incidence of hyperkalaemia reported in observational studies”. Clinical Kidney Journal, 2022, 15(4):727-737). A real-world study in Japan showed that the prevalence of hyperkalemia in CKD 3a, 3b, 4, and 5 was 13.22%, 24.56%, 43.65%, and 51.19% respectively (Kashihara N et.al. “Hyperkalemia in Real-World Patients Under Continuous Medical Care in Japan”, Kidney International Reports, 2019 May 30;4(9):1248-1260).

[0005] The treatment methods of hyperkalemia include calcium agent, insulin, glucose, calcium bicarbonate, beta-adrenergic, diuretics, dialysis treatment, cation exchange resin, new ion exchange polymer, low potassium diet, etc. Although intravenous administration can quickly reduce blood potassium level by transferring potassium ions to cells, it does not change the total amount of potassium in the body, and the maintenance time is short, and rebound is easy. The low potassium diet recommended by the guidelines has low compliance, is difficult to implement, and may increase the risk of cardiovascular event-related death. Diuretics that promote the excretion of potassium ions by the kidneys have no selectivity for ions, and long-term use can cause patients to have reduced kidney function and exacerbate hyperkalemia. Potassium-lowering resin that excretes potassium ions through the intestinal tract is a less harmful treatment method, especially non-absorbed polymer drugs, which are only excreted through the gastrointestinal tract and have more advantages in safety. However, there are very limited existing such drugs, and there are currently three approved drugs.

[0006] The product of Concordia Pharmaceutical Inc. under the trademark was approved by the US FDA in 1958 for the treatment of hyperkalemia, and is administered orally or rectally. For oral administration, the daily dose is 15-60 g, administered at a dose of 15 g (four flat spoons), 1-4 times a day. It is presented as a cream to a light brown fine powder, stored in a 1 pound (453.6 g) can. The active ingredient is sodium polystyrene sulfonate, a cation exchange resin containing sodium counterions, with the following chemical structure:

[0007] For oral administration, it is suspended in water or syrup at a ratio of about 2-4 ml of liquid per gram of resin, and consumed within 24 hours. It should be stored at a controlled temperature, more specifically, It should be stored at 25°C, with an allowable deviation range of 15°C to 30°C.

[0008] The product of Vifor Pharma, Inc. under the trademark was approved by the US FDA in 2015 for the treatment of hyperkalemia, and is administered orally. is a powder packed in a small bag with an aluminum foil liner, composed of patiromer sorbitol calcium and xanthan gum, used to make a suspension in water, and then immediately administered orally. The chemical structure of patiromer sorbitol calcium is as follows:

[0009] wherein m is the number of 2-fluoro-2-propenoic acid groups, m = 0.91; n, p are the number of cross-linking groups, n + p = 0.09; • H2O is bound water; * indicates a derivatized polymeric network. Patiromer calcium sorrel is not soluble in aqueous liquids, the active moiety is patiromer, 1 g of patiromer is equivalent to 2 g of labeled patiromer calcium sorrel per pouch contains 8.4 g, 16.8 g or 25.2 g of patiromer (1 g of patiromer is equivalent to 2 g of labeled patiromer calcium sorrel). It should be stored in the refrigerator at 2-8 °C, if stored at room temperature (25 °C ± 2 °C), must be used within 3 months, the storage temperature cannot exceed 40 °C. It is also prohibited for patients to add to hot food or liquids. The usage is as follows: measure 1 / 3 cup of water, pour half of the water into a glass, then add and stir. Add the remaining half of the water, stir well. The powder will not dissolve, the mixture will look cloudy. Add more water to the mixture as needed to achieve the desired consistency. Drink the mixture immediately. If there is powder left in the glass after drinking, add water, stir and drink immediately. Repeat the above steps as needed to ensure that the entire dose is taken. It can be seen that has poor storage stability, it is not easy to store in areas and seasons with higher temperatures, and has a long dispersion time and poor dispersibility, when the drug powder is added to water, it is obvious that there is agglomeration even under stirring, it is not easy to disperse, in order to ensure the required dose, the patient often needs to drink a large amount of water, which is not suitable for CKD patients who have strict control on the amount of water. Moreover, the drug needs to be drunk immediately after dispersion in water, it cannot be stored.

[0010] AstraZeneca's trademark is was approved by the US FDA in 2018 for the treatment of hyperkalemia in adults, oral administration. The active ingredient of is sodium zirconium cyclosilicate, its chemical formula is Na ～1.5 H ～0.5 ZrSi3O9·2-3H2O. is a white to gray powder, packed in small bags with aluminum foil lining. The usage method of is: pour the entire contents of the bag into a glass containing about 3 tablespoons of water or more water. Stir well and drink immediately. If there is still powder in the water glass, add water, stir and drink immediately. Repeat the above steps until there is no powder left, the entire dose is taken. It also needs to be stored under controlled conditions, with a storage temperature of 15°C to 30°C.

[0011] Therefore, there is still an urgent clinical need for new, easily stored and administered non-absorbable drugs for the treatment of hyperkalemia. Summary of the Invention

[0012] The present invention satisfies the above-mentioned requirements by providing a dry suspension containing poly(2-fluoroacrylate-Pentaerythritol triallyl ether) Calcium Ferric Sodium salt.

[0013] Sodium iron calcium salt of poly(2-fluoroacrylate-pentaerythritol triallyl ether) and The active ingredient, palteromoride calcium, belongs to the same class of drugs, both being cation exchange polymers. They share similar physical properties (such as particle shape, surface morphology, and swelling ratio) and both treat hyperkalemia by binding potassium in the gastrointestinal tract.

[0014] although It is widely used in clinical practice, but it has significant drawbacks. On the one hand, Store in a refrigerator at 2°C to 8°C. If stored at room temperature (25°C ± 2°C), Must be used within 3 months, storage temperature must not exceed 40℃, and must not be exposed to light. Heated or added to hot food or liquid. Therefore, Its storage stability is poor, and it is not suitable for long-term storage in areas and seasons with high temperatures. On the other hand, The dispersion time is long and the dispersibility is poor. When the drug powder is added to water, it clearly clumps together even with stirring, making it difficult to disperse. To ensure the required dosage, patients often need to drink plenty of water. Moreover, the drug must be consumed immediately after dispersion in water and cannot be stored, otherwise precipitation will occur quickly. Therefore, Patients find it inconvenient to use and have poor compliance.

[0015] The inventors discovered that for powder formulations that may be used in high doses, improving agglomeration and poor dispersibility by adding large amounts of fillers such as mannitol, lactose, or microcrystalline cellulose or increasing the volume of dispersible water would further increase the burden on patients and reduce compliance. If this problem is solved by adding small amounts of disintegrants such as sodium croscarmellose, sodium carboxymethyl starch, croscarmellose, or low-substituted hydroxypropyl cellulose (i.e., improving dispersibility by increasing the hygroscopicity of the powder), the disintegrant components will slowly absorb moisture during storage, leading to poor dispersibility.

[0016] In the course of investigating the formulation of a dry suspension of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, the inventors unexpectedly found that the addition of a small amount of silicon dioxide or a substance containing silicon dioxide such as a solid powder flavor significantly reduces the dispersion time of the dry suspension, improves the problem of clumping, and maintains these technical effects without being impaired over a long period of storage. The solid powder flavor is generally used as a fragrance (an aromatic substance that improves the taste and odor of a pharmaceutical preparation) in the pharmaceutical industry, and has never been found to have the effect of improving the dispersibility and stability of a polymer. The dry suspension of the present application greatly reduces the preparation time and the amount of drinking water required for a patient to take the dry suspension, thereby improving the patient's compliance, and enables the dry suspension of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt to be used as a dry suspension. has a longer storage period and improved stability compared to storage under room temperature conditions.

[0017] Definitions

[0018] The terms used herein have the meanings defined below, and the terms not defined herein have the usual meanings in the art.

[0019] The term "about", "approximately" when used in connection with a numerical value means ± 5% of the numerical value with which it is used, i.e., the numerical value with which it is used is extended to a range having a lower limit of 95% of the numerical value and an upper limit of 105% of the numerical value.

[0020] The terms "comprising", "containing", "including" used herein mean including the recited elements, numerical values or steps, but do not exclude any other elements, numerical values or steps. In this context, the terms "comprising", "containing", "including" also encompass the case where the recited elements, numerical values or steps are essential, i.e., the terms "comprising", "containing", "including" also encompass "consisting essentially of" and "consisting of", unless otherwise stated. In the context of defining the components of the dry suspension of the present application, the term "consisting essentially of" means that only a small amount (e.g., ≤ 10%, ≤ 8%, ≤ 5%, ≤ 3%, ≤ 2%, ≤ 1%, or ≤ 0.5% and > 0%) of other components in addition to the components explicitly listed are included and the small amount of other components does not affect the performance, use or therapeutic effect of the dry suspension of the present application; the term "consisting of" means that no other components are included in addition to the components explicitly listed.

[0021] The term "poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) calcium ferric sodium salt" as used herein refers to the cross-linked polymer of Calcium Ferric Sodium 2-fluoroacrylate with Pentaerythritol triallyl ether prepared in Example 3 of PCT application WO2023 / 088111A1, the simplified structural schematic of which is as follows:

[0022] wherein m = 0.95, and n = 0.05,

[0023] Also referred to in this application as "polymer salt of the invention" or "MFA-APE-Na-Ca-Fe".

[0024] In Example 3 of PCT application WO2023 / 088111A1, the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) calcium ferric sodium salt was prepared using the following method:

[0025] Into a reaction flask was added purified water (550 mL), NaCl (11.0 g), and polyvinyl alcohol (3.4 g) and stirred at 20-30 °C until completely dissolved to give a clear solution. A 2-fluoroacrylate (MFA) solution was prepared by stirring and completely dissolving 104.0 g MFA (1.0 mol), 12.8 g pentaerythritol triallyl ether (APE) (0.05 mol), and 0.73 g benzoyl peroxide (0.003 mol) to give a clear solution, which was ready for use. The prepared MFA solution was added to the solution in the reaction flask. The temperature of the contents of the reaction flask was gradually increased to 70-80 °C, after which the temperature was maintained and stirring was continued for 15 hours. Gas chromatography monitoring showed that the reaction was complete. After the temperature was reduced to 20-30 °C, suction filtration was performed. The filter cake was slurried and washed with water and ethanol. The resulting wet product was dried at 50 °C under vacuum to give 97.3 g of a white solid, which was the MFA-APE ester polymer.

[0026] Into a reaction flask was added 400 mL water, 130 mL EtOH, and 48.0 g sodium hydroxide, followed by the above MFA-APE ester polymer with stirring. The temperature was increased to 50-60 °C, after which the temperature was maintained with stirring for 15 hours. The temperature was reduced to 20-30 °C, after which filtration was performed, and the filter cake was slurried and washed with water and ethanol, and filtered to give the wet MFA-APE sodium salt polymer (MFA-APE-Na).

[0027] To a reaction flask, 500 mL of water and 100 mL of concentrated hydrochloric acid were added, followed by the addition of the above wet MFA-APE sodium salt polymer, and then stirred at 20-30°C for 15 hours. After filtration, the filter cake was washed repeatedly with 4 L of water, filtered, to obtain a wet MFA-APE acid polymer (MFA-APE-H).

[0028] To the above acid polymer, 240 mL of water was added and stirred at 10-30°C. To this mixture, FeCl3(0.7 g), Ca(OH)2(18.0 g) and NaOH (9.6 g) were slowly added, controlling the internal temperature at 10-30°C. The mixture was stirred for 2-5 hours, and then the mixture was filtered to obtain a wet solid. The wet solid was slurried with 2 L of water. After filtration, the resulting wet filter cake was dried at 50°C under vacuum for 8 hours to obtain 99.0 g of a yellow dry product, which was pulverized and sieved through a 120 mesh screen to obtain a MFA-APE Na-Ca-Fe complex salt polymer (m=0.95, n=0.05) (MFA-APE-Na-Ca-Fe).

[0029] Poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt is a non-absorbed oral macromolecular polymer with high selectivity for K + binding in the gastrointestinal tract, K + and excreted out of the body with feces, thereby reducing blood potassium levels. In vitro tests under simulated human body environment, the amount of potassium ion binding by the polymer salt of the present invention is The polymer salt of the present application significantly reduces the serum potassium level of rats in a hyperkalemia rat model, increases the excretion of potassium ions in feces, and can effectively treat hyperkalemia in rats. The pharmacokinetic study results show that after a single gavage of 300 mg / kg of the polymer salt of the present application to rats, the total drug-related substance concentration in the plasma at different time points within 24 hours after administration is lower than the lower limit of quantification, indicating that the polymer salt of the present application is not absorbed into the blood. The tissue distribution study results show that after a single gavage of 300 mg / kg to rats, the drug-related substances are mainly concentrated in the contents of the large intestine, stomach and small intestine, and have been basically eliminated 48 h after administration. The substance balance experiment results show that the polymer salt of the present application is completely excreted out of the body through feces. In addition, the toxicology study shows that after a single gavage of 3000 mg / kg, 6000 mg / kg, 9000 mg / kg to rats, the rats are observed for 2 weeks, and no abnormalities are found in the overall condition, spontaneous activity, body weight, fur, food intake, and no abnormal changes are found in various organs or tissues, and the rats tolerate well, and no toxicity is observed. The repeated dose toxicity test on Beagle dogs also produces the same results, and no toxicity is found, and the safety and tolerance are good. The phase I clinical and phase II clinical of the polymer salt of the present application show that when the dry suspension of Example 6 of the present application is administered to subjects, the polymer of the present application effectively reduces the serum potassium concentration to the normal range without obvious side effects, the safety and tolerance are good, and the patients have good compliance when administered at a regimen of 3-48 g / time, three times a day for two days, and optionally continuing to administer at a daily dose of 3-48 g, preferably 6-18 g, once a day.

[0030] The term "individual" as used herein refers to an animal. Preferably, the individual is a mammal, such as a primate (e.g., a human, a monkey, a chimpanzee), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, etc. More preferably, the individual is a human, in particular an adult human.

[0031] The terms "serum potassium" and "blood potassium" as used herein can be used interchangeably, and both refer to the serum potassium level.

[0032] The term "treatment" as used herein refers to significantly reducing the serum potassium level of an individual, in particular bringing the serum potassium level of an individual to the normal range of 3.5-5.0 mmol / L.

[0033] The term "room temperature" as used herein refers to 15-30 °C, in particular 25 °C.

[0034] The term "silica" as used herein refers to a pharmaceutically acceptable silica, for example, silica with trade name The term "silica" as used herein refers to a pharmaceutically acceptable silica, for example, silica with trade name 200), or other commercially available silicas, such as Grace manufactured silica with model number 244FP, Anhui Shanhel Pharmaceutical Auxiliary Co., Ltd. manufactured silica with model number SH-QX1, etc.

[0035] Embodiments

[0036] In a first aspect, the present application provides a dry suspension for treating hyperkalemia, the dry suspension comprising:

[0037] (i) poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt,

[0038] (ii) a suspending agent, and

[0039] (iii) a solid powder flavor comprising silica,

[0040] wherein the suspending agent is preferably selected from one or more of xanthan gum, sodium alginate, propylene glycol alginate, and the suspending agent comprises > 0.5% by weight of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, such as 0.5% to 20%, 0.5% to 15%, 0.5% to 10%, 0.5% to 5%, 0.5% to 2%,

[0041] wherein the silica comprises > 0.05% to < 3% by weight of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, such as > 0.05% to < 3%, such as > 0.05% to 2.5%, 0.06% to 2.4%, 0.07% to 2.3%, 0.08% to 2.2%, 0.09% to 2.1%, or 0.1 to 2%.

[0042] In one embodiment of the first aspect, the suspending agent is xanthan gum.

[0043] The solid powder flavor comprising silica refers to a solid powder flavor commonly used in the art, which comprises or consists of silica, glucose and a flavor, wherein the silica usually accounts for 10-80% by weight of the total weight of the solid powder flavor, such as 10-50%, 10-30% or 10-20%. The flavor determines the scent presented by the solid powder flavor, for example, according to the different components of the flavor, the solid powder flavor consisting of silica can be selected from lime powder flavor, strawberry powder flavor, lemon powder flavor and mixtures thereof in any proportion.

[0044] The solid powder flavor is commercially available. For example, lime powder flavor can be purchased from Sunxin Flavor Pigment Technology (China) Co., Ltd., which consists of silica, glucose and a flavor, wherein the silica accounts for 10%-20% by weight of the lime powder flavor.

[0045] In the above embodiments of the first aspect, the weight ratio of the suspending agent (in particular xanthan gum) to the silicon dioxide is from 20:1 to 1 :2.5 (e.g. 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11 :1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1 :1, 1 :2, 1 :2.5), preferably from 15:1 to 1 :2, more preferably from 10:1 to 1 :2.

[0046] In the above embodiments of the first aspect, the dry suspension is for oral administration after dispersion in water, for example, administration after dispersion in water having a temperature of no more than 60 °C.

[0047] In the above embodiments of the first aspect, the dry suspension contains from 1 to 6 g, for example 1 g, 3 g or 6 g of poly(2-fluoroallylic acid-pentaerythritol triallyl ether) iron calcium sodium salt per sachet.

[0048] In the second aspect, the present application provides a process for preparing the dry suspension of the present application, characterized in that,

[0049] When component (iii) is silicon dioxide, the process comprises the following steps: (1) mixing all components and passing through a 100 mesh sieve to obtain the dry suspension; optionally, (2) filling the dry suspension obtained in step (1) into sachets, each sachet containing from 1 to 6 g, for example 1 g, 3 g or 6 g of poly(2-fluoroallylic acid-pentaerythritol triallyl ether) iron calcium sodium salt;

[0050] When component (iii) is a solid powder flavour, the process comprises the following steps: (1) pulverizing the solid powder flavour and passing through a 100 mesh sieve to obtain a powder; (2) mixing poly(2-fluoroallylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, suspending agent and the powder obtained in step (1) and passing through a 100 mesh sieve to obtain the dry suspension; optionally, (3) filling the dry suspension obtained in step (2) into sachets, each sachet containing from 1 to 6 g, for example 1 g, 3 g or 6 g of poly(2-fluoroallylic acid-pentaerythritol triallyl ether) iron calcium sodium salt.

[0051] In the third aspect, the present application provides the use of the dry suspension of the first aspect for the preparation of a medicament for the treatment of hyperkalemia.

[0052] In the fourth aspect, the present application provides a method for the treatment of hyperkalemia, the method comprising administering to a patient a therapeutically effective amount of the dry suspension of the present application of the first aspect.

[0053] A clinician can determine the amount of the dry suspension of the present application to be administered and the frequency and duration of administration, in accordance with the age, sex, weight, serum potassium level, concurrent medication, and the like, of the patient, so as to maintain the serum potassium concentration of the patient within the normal range of 3.5-5.0 mmol / L. For example, the therapeutically effective amount can be 3-48 g of poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt; preferably, the therapeutically effective amount is 6-18 g of poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt. The therapeutically effective amount can be administered once or more times per day, for example, once or three times; alternatively, the therapeutically effective amount can be administered once every other day.

[0054] In one embodiment of the fourth aspect, the method comprises a first phase dosing regimen and optionally a second phase dosing regimen, wherein the first phase dosing regimen is oral administration of poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt to the individual 3 times per day at 3-48 g (e.g., 3 g, 6 g, 9 g, 12 g, 15 g, 18 g, 21 g, 24 g, 27 g, 30 g, 33 g, 36 g, 39 g, 42 g, 45 g, 48 g), preferably 6-48 g, 6-36 g, 6-24 g, or 6-18 g, for 2 consecutive days; and the second phase dosing regimen is oral administration of poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt to the individual at 3-48 g (e.g., 3 g, 4 g, 5 g, 6 g, 9 g, 12 g, 15 g, 18 g, 21 g, 24 g, 27 g, 30 g, 33 g, 36 g, 39 g, 42 g, 45 g, 48 g), preferably 4-48 g, 5-48 g, or 6-48 g, more preferably 6-24 g, 6-18 g, once per day or once every other day.

[0055] In another embodiment of the fourth aspect, the method comprises a first phase dosing regimen and optionally a second phase dosing regimen, wherein the first phase dosing regimen is oral administration of poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt to the individual 3 times per day at 12 g for 2 consecutive days; and the second phase dosing regimen is oral administration of poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt to the individual once per day at 6-18 g. Examples

[0056] The following examples are intended to illustrate the present application but not to limit the scope of the claims in any way.

[0057] Examples 1-23: Composition and preparation of dry suspensions comprising poly(2-fluoroallyl acid-pentaerythritol triallyl ether) iron calcium sodium salt

[0058] *Purchased from Senxin Fragrance & Pigment Technology (China) Co., Ltd., product number: 98AF6461, composed of silicon dioxide, glucose and fragrance, of which silicon dioxide accounts for 10%-20% by weight of the sour orange powder fragrance.

[0059] The dry suspensions of Examples 3-9 were prepared as follows:

[0060] (1) Grind the sour orange powder flavoring into powder and pass it through a 100-mesh sieve to obtain powder;

[0061] (2) Weigh the required amount of poly(2-fluoroacrylate-pentaerythritol triallyl ether) iron calcium sodium salt and other components and the powder obtained in step (1), and add them to a three-dimensional mixer and mix at 10 rpm for 5 min to obtain a mixture;

[0062] (3) Pass the mixture obtained in step (2) through a 100-mesh sieve, and then mix at 10 rpm for 5 min to obtain the final mixture;

[0063] (4) The final mixture obtained in step (3) is filled into small bags with aluminum foil lining, each bag containing 3g of poly(2-fluoroacrylate-pentaerythritol triallyl ether) iron calcium sodium salt to obtain a dry suspension.

[0064] The dry suspensions of Examples 14-21 were prepared as follows:

[0065] (1) Weigh the required amount of poly(2-fluoroacrylate-pentaerythritol triallyl ether) iron calcium sodium salt, silica and other components, add them to a three-dimensional mixer, mix at 10 rpm for 5 min to obtain a mixture;

[0066] (2) Pass the mixture obtained in step (2) through a 100-mesh sieve, and then mix at 10 rpm for 5 min to obtain the final mixture;

[0067] (3) The final mixture obtained in step (3) is filled into small bags with aluminum foil lining, each bag containing 3g of poly(2-fluoroacrylate-pentaerythritol triallyl ether) iron calcium sodium salt to obtain a dry suspension.

[0068] The dry suspensions of Examples 1-2, 10-13, and 22-23 are prepared as follows:

[0069] (1) Weigh the required amount of poly(2-fluoroacrylate-pentaerythritol triallyl ether) iron calcium sodium salt and other ingredients in the prescription table, add them to a three-dimensional mixer, mix at 10 rpm for 5 min to obtain a mixture;

[0070] (2) The mixture obtained in step (2) was passed through a 100 mesh sieve and then mixed at 10 rpm for 5 min to obtain a final mixture;

[0071] (3) The final mixture obtained in step (3) was filled into sachets with aluminum foil inner liner, each sachet containing 3 g of poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt to obtain a dry suspension.

[0072] The composition of each sachet of the dry suspension of Example 6 is as follows:

[0073] Example 24: Measurement of water dispersing speed

[0074] The content of one sachet of the dry suspension prepared in Examples 1-23 was poured into a container containing 20 ml of water, and stirred at a speed of 120 rpm using an overhead stirring disperser, with the stirring paddle placed at half the height of the liquid and in the center. The time for the formation of lumps and the time for the powder to be completely dispersed by stirring were recorded.

[0075] The content of one sachet of commercially available was weighed at 3.06 g, and the dispersing speed was measured in the same way as in Examples 1-23.

[0076] The results are shown in the following table: Note: (1) min = minute, s = second (2) The lime powder essence used for mixing with VELTASSA was also purchased from Sunwin Fragrance & Color Technology (China) Co., Ltd., product number: 98AF6461, which was composed of silica, glucose and flavor, and the silica accounted for 10-20% of the lime powder essence by weight.

[0077] (3) The dry suspension containing was prepared in a similar way as in Examples 1-23.

[0078] The results obtained in Examples 1 to 9 and 14 to 18 show that a dry suspension comprising poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, xanthan gum and > 0.05 wt% of silicon dioxide, based on the weight of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, is completely dispersed in a short time without the formation of aggregates, which is significantly better than a dry suspension without silicon dioxide or with < 0.05 wt% of silicon dioxide. The experimental results obtained in Examples 10 to 13 show that the replacement of silicon dioxide by the corresponding amount of cross-linked sodium carboxymethylcellulose, cross-linked povidone, sodium carboxymethyl starch or low-substituted hydroxypropyl cellulose results in a dry suspension with poor dispersion properties. The experimental results obtained in Example 19 show that the amount of silicon dioxide should be < 3% based on the weight of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, otherwise the dispersion properties of the dry suspension are adversely affected. The results obtained in Examples 22 and 23 show that the replacement of xanthan gum as suspending agent by propylene glycol alginate or sodium alginate results in a suspension which still has good dispersion properties. The results obtained in Examples 17, 20 and 21 show that the origin of the silicon dioxide has no significant influence on the dispersion properties of the dry suspension. Surprisingly, the use of commercially available products and The experimental results obtained with mixtures of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt of the application and 0.5% or 1% of a bergamot powder essence, based on the weight thereof, show that the same amount of silicon dioxide does not result in a polymer product similar to the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt of the application in a good dispersion.

[0079] This more advantageous aqueous dispersion of the dry suspension of the application leads to a convenient use and a significant increase in patient compliance.

[0080] Example 25: Determination of the potassium ion binding capacity

[0081] Blank solution: deionized water.

[0082] Potassium binding solution: Weigh out 9.35 g ± 0.93 g of potassium hydroxide and 45.5 g ± 4.55 g of morpholine ethanesulfonic acid, place in a 1 L beaker, dissolve with ultrasonic treatment, transfer in small amounts to a 1 L volumetric flask with deionized water, dilute to the mark with deionized water, measure the pH, which should be between 6.45 and 6.54, if the pH is not in the required range, the solution must be prepared again. (The potassium ion concentration is approximately 150 mmol / L).

[0083] Linear solution: Dilute the potassium binding solution with deionized water to obtain dilution solutions with a potassium ion concentration of approximately 0.3 mmol / L, 0.9 mmol / L, 1.5 mmol / L, 2.4 mmol / L and 3 mmol / L, inject into the ion chromatograph to obtain a standard curve.

[0084] Test solution: Weigh 1.6g ± 0.16g of sample and place it in a 250ml iodine flask. Accurately add 100ml of potassium binding solution and stir with a magnetic stirrer in a water bath (37℃ ± 0.5℃) for 3 hours. Remove, cool, and mix well. Take about 4ml and place it in a 10ml EP tube. Centrifuge at 4000rpm for 5 minutes. Accurately measure 0.5ml of the supernatant and place it in a 25ml volumetric flask. Dilute to the mark with deionized water and mix well. Take about 4ml of the solution and place it in a 30KD ultrafiltration centrifuge tube. Centrifuge at 4000rpm for 5 minutes. Inject the filtrate into the ion chromatograph. Prepare two parallel aliquots.

[0085] The amount of potassium ion adsorption was calculated using the standard curve method.

[0086] Ion chromatograph conditions:

[0087] The results are shown in the table below:

[0088] The results of this embodiment show that the excipients in the dry suspension do not affect the potassium ion binding capacity of poly(2-fluoroacrylate-pentaerythritol triallyl ether) iron-calcium sodium salt. Furthermore, the potassium ion binding capacity of the dry suspension of the present invention is not less than...

[0089] Example 26: Stability after preparation and storage

[0090] Take 18.36g of the dry suspension from Example 6 above, add 90ml of water at different temperatures, and test the stability indicators. The results show that the stability of the dry suspension from Example 6 does not show obvious trends in water at 25℃, 37.5℃, and 60℃, and the storage stability after preparation is good. The specific experimental results are as follows:

[0091] Example 27: Storage Stability

[0092] The dry suspension samples from Examples 5-9, 14, 18, and 20-23, after being scaled up in batches, were stored at 25℃±2℃ and 60%RH±5%RH for 6 months. All stability test items showed changes within the required range, indicating good stability. Specific experimental data are as follows:

[0093] Table 1: Stability test data of Example 6

[0094] Table 2: Stability test data of Example 5

[0095] Table 3: Stability test data of Example 7

[0096] Table 4: Stability test data of Example 8

[0097] Table 5: Stability test data of Example 9

[0098] Table 6: Stability test data of Example 14

[0099] Table 7: Stability test data of Example 18

[0100] Table 8: Stability test data of Example 20

[0101] Table 9: Stability test data of Example 21

[0102] Table 10: Stability test data of Example 22

[0103] Table 11: Stability test data of Example 23

[0104] The data in the tables above show that the dry suspension of the present invention can be stored for at least 6 months under accelerated conditions of 25℃±2℃ and 60%RH±5%RH, and its physical and chemical properties remain stable.

[0105] The dry suspensions prepared in Examples 5-9, 14, 18, and 20-23 were stored at 25°C ± 2°C and 60% RH ± 5% RH for 6 months. Samples were taken at different time points, and their stability was determined according to the method described above. Surprisingly, it was found that the physical and chemical stability of these dry suspensions remained almost unchanged after storage for up to 6 months.

[0106] This proves that, compared to similar products that can only be stored for 3 months at 25°C, this is significantly better. Compared to the present invention, the dry suspension exhibits significantly improved storage stability.

[0107] The foregoing describes exemplary embodiments of the present invention. Those skilled in the art should understand that these disclosures are merely exemplary, and various other substitutions, adaptations, and modifications can be made within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments listed herein.

Claims

1. A dry suspension for oral administration comprising: (i) poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, (ii) a suspending agent, and (iii) silicon dioxide or a solid powder flavour comprising silicon dioxide.

2. The dry suspension according to claim 1, wherein the suspending agent is selected from one or more of xanthan gum, sodium alginate, propylene glycol alginate.

3. A dry suspension according to any one of claims 1 to 2 wherein, The silicon dioxide is present in an amount of > 0.05% to < 3%, for example > 0.05% to < 3%, for example > 0.05% to 2.5%, 0.06% to 2.4%, 0.07% to 2.3%, 0.08% to 2.2%, 0.09% to 2.1%, or 0.1 to 2% by weight of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt.

4. A dry suspension according to any one of claims 1 to 3 wherein, The suspending agent is present in an amount of > 0.5%, for example 0.5% to 20%, 0.5% to 15%, 0.5% to 10%, 0.5% to 5%, 0.5% to 2% by weight of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt.

5. A dry suspension according to any one of claims 1 to 4 wherein, The solid powder flavour is selected from one or more of lime powder flavour, strawberry powder flavour, lemon powder flavour.

6. A dry suspension according to any one of claims 1 to 5 wherein, The weight ratio of the suspending agent (in particular xanthan gum) to silicon dioxide is 20: 1 to 1:2.5, preferably 15: 1 to 1:2, more preferably 10: 1 to 1:

2.

7. A dry suspension according to any one of claims 1 to 6 wherein, The dry suspension is for oral administration after dispersion in water.

8. A dry suspension according to any one of claims 1 to 7 wherein, The dry suspension is packaged in sachets, each sachet containing 1-6 g, for example 1 g, 3 g or 6 g of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt.

9. A process for the preparation of the dry suspension of any one of claims 1 to 7, characterised in that: when component (iii) is silicon dioxide, the process comprises the following steps: (1) mixing all components and sieving through a 100 mesh sieve, to obtain the dry suspension; optionally, (2) filling the dry suspension obtained in step (1) into sachets, each sachet containing 1-6 g, for example 1 g, 3 g or 6 g of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt; when component (iii) is a solid powder flavour, the process comprises the following steps: (1) comminuting the solid powder flavour and sieving through a 100 mesh sieve to obtain a powder; (2) mixing the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt, the suspending agent and the powder obtained in step (1) and sieving through a 100 mesh sieve, to obtain the dry suspension; optionally, (3) filling the dry suspension obtained in step (2) into sachets, each sachet containing 1-6 g, for example 1 g, 3 g or 6 g of the poly(2-fluoroacrylic acid-pentaerythritol triallyl ether) iron calcium sodium salt.

10. Use of the dry suspension of any one of claims 1 to 8 for the manufacture of a medicament for the treatment of hyperkalemia.

11. A method of treating hyperkalemia in a patient, the method comprising administering to the patient a therapeutically effective amount of the dry suspension of any one of claims 1 to 8, wherein the therapeutically effective amount is 3-48 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt, preferably 6-18 g of poly(2-fluoropropenoic acid-pentaerythritol triallyl ether) iron calcium sodium salt, which can be administered once or multiple times (e.g., one to three times) per day; or the therapeutically effective amount can be administered once every other day, to bring the patient’s serum potassium concentration within the normal range of 3.5-5.0 mmol / L.

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