Preparation method of sevelamer carbonate tablets

Abstract

The invention relates to a sevelamer carbonate tablet and a preparation method thereof. The preparation method comprises the following steps: carrying out wet granulation on calcium carbonate, microcrystalline cellulose (internally added) and purified water, and carrying out dry granulation on the prepared particles, sevelamer carbonate, microcrystalline cellulose (externally added) and magnesium stearate. The prepared tablet has good moisture uniformity and low hygroscopicity, the storage stability is improved, meanwhile, standing balance is not needed, the preparation time is greatly shortened, the production efficiency is improved, and a new thought is provided for mass production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a method for preparing sevelamer carbonate tablets. Background Technology

[0002] Phosphorus (P) plays an important physiological role in the human body. It is mainly derived from daily diet, with the majority deposited in bones as calcium phosphate, a crucial component of bones and teeth. Only a small portion of phosphorus exists in body fluids; inorganic phosphorus is usually present in serum, playing a vital role in maintaining acid-base balance. Approximately 70% of phosphorus is excreted through the kidneys; therefore, kidney failure can lead to hyperphosphatemia. While dialysis can partially replace normal kidney function in patients with chronic kidney disease, the limited frequency of hemodialysis and the limited phosphorus removal capacity of peritoneal dialysis prevent the sufficient removal of absorbed phosphorus, ultimately leading to a continuous increase in serum phosphorus concentration and hyperphosphatemia. Hyperphosphatemia itself does not produce specific clinical symptoms; its effects on the body mainly include secondary elevation of the calcium-phosphorus product, hypocalcemia, and hyperthyroidism, thereby triggering a series of clinical symptoms.

[0003] Sevelamer carbonate can be used to control serum phosphorus levels in patients with chronic kidney disease undergoing hemodialysis. It is a phosphate-bound cross-linked polymer that is not absorbed by the human body. Sevelamer carbonate reduces serum phosphate concentration by binding to phosphate groups in the digestive tract and reducing their absorption, thereby lowering serum phosphorus levels.

[0004] The National Medical Products Administration (NMPA) has published the reference formulation for sevelamer carbonate tablets in its 22nd batch of generic drug reference preparations. The product is marketed as Novella, and its patent US7985418B2 describes a wet granulation process requiring a 24-hour settling period after granulation. This 24-hour settling process results in low production efficiency and lacks a drying process. The product has a moisture content limit of 14%. Sevelamer carbonate raw material is highly hygroscopic; directly adding water during granulation makes the reaction between the raw material and water uncontrollable. This process easily leads to uneven moisture distribution and severe hygroscopicity in the product.

[0005] Chinese patent CN104739786A discloses a sevelamer carbonate tablet and its preparation method. The process involves "mixing the prescribed amount of microcrystalline cellulose, water, and sodium carbonate evenly and equilibrating for 8 hours, then mixing it evenly with the prescribed amount of sevelamer carbonate, adding zinc stearate, and compressing into tablets." Compared with the original patent, this process shortens the settling time, but it still affects production efficiency, and the product still carries the risk of uneven moisture distribution.

[0006] Chinese patent CN103393610A discloses a formulation and preparation method for sevelamer carbonate tablets, which states that "sevelamer carbonate, microcrystalline cellulose, sodium bicarbonate, arginine, and polylactic acid are mixed evenly, water is added and mixed evenly, dry granulation is performed, magnesium stearate is added, mixed evenly, and then compressed into 1000 tablets to obtain the product." This dry granulation process still involves directly mixing water with the raw materials, and the final product still carries a high risk of uneven moisture distribution. Summary of the Invention

[0007] Objective of the Invention: To improve the moisture uniformity of sevelamer carbonate tablets and reduce the product's hygroscopicity, it is necessary to develop a novel formulation and optimize the preparation of tablets with qualified quality, simple process, and safe formulation using a novel process. This application provides a formulation composition and preparation method for sevelamer carbonate tablets. This method significantly reduces the safety risks of the formulation, and the process is simple, with a short preparation time, requiring no drying or settling, making it suitable for large-scale production. Using a dry granulation process can improve the production efficiency of this product.

[0008] The objective of this invention is achieved through the following technical solution, comprising the following steps: This product is a sevelamer carbonate tablet, the formulation of which contains the following components by weight: Sevelamer carbonate 70% Calcium carbonate 5% 9% corn starch Microcrystalline cellulose (added internally) 8% Microcrystalline cellulose (added) 7% 1% magnesium stearate Another object of the present invention is to provide a method for preparing the above-mentioned tablets, comprising the following steps: (1) Take the prescribed amount of corn starch and the prescribed amount of calcium carbonate and microcrystalline cellulose (added internally) for wet granulation. Set the stirring speed to 300 rpm and the shearing speed to 1500 rpm. The characteristic is that the amount of purified water added is 15%~25% of the total weight of the materials. After granulation, the soft material is granulated by passing it through a 20-mesh sieve and then set aside as granules 1.

[0009] (2) Take sevelamer carbonate, microcrystalline cellulose (added), and the above-mentioned granules 1, mix them in a mixer for 10 min, add 0.5% magnesium stearate and mix for 5 min, then perform dry granulation. Set the oil pressure to 0-7 MPa, the conveying speed to 20-40 rpm, and the pressure roller speed to 15 rpm. Use an 18-mesh sieve and a granulation speed of 50-80 rpm.

[0010] (3) After dry granulation, add the remaining 0.5% magnesium stearate to the granules, mix them together in a mixer, and then compress them into tablets.

[0011] The method described in this invention is characterized by avoiding direct contact and reaction between sevelamer carbonate and purified water. Corn starch, microcrystalline cellulose, and calcium carbonate are added as fillers and granulated with a certain amount of purified water to give the material a certain moisture content and viscosity. Then, it is mixed evenly with dry raw materials, granulated by dry granulation, and then granulated again with the raw materials. After compression into tablets, the product is ready. Detailed Implementation

[0013] During their research, the inventors discovered that the key process parameter for this invention is the amount of purified water added during wet granulation. Insufficient water results in a lack of viscosity in the material, making subsequent dry granulation impossible. Excessive water, on the other hand, leads to tablets with excessive moisture content. The microcrystalline cellulose used in this invention's formulation is ZW-112, which has a low moisture content (less than 1%), making it suitable for water-sensitive active ingredients. The invention will now be described in further detail with reference to specific embodiments. These embodiments are provided for illustrative purposes only and are not intended to demonstrate the scope of the invention.

[0014] Example 1 prescription prescription Sevelamer carbonate 70% Calcium carbonate 5% 9% corn starch Microcrystalline cellulose (added internally) 8% Microcrystalline cellulose (added) 7% 1% magnesium stearate Preparation process (1) Take the prescribed amount of corn starch and the prescribed amount of calcium carbonate and microcrystalline cellulose (added internally) for wet granulation. Set the stirring speed to 300 rpm and the shearing speed to 1500 rpm. Add purified water at 15% of the total weight of the materials. After granulation, the soft material is granulated through a 20-mesh sieve and set aside as granules 1.

[0015] (2) Take sevelamer carbonate, microcrystalline cellulose (added), and the above-mentioned granules 1, mix them in a mixer for 10 min, add 0.5% magnesium stearate and mix for 5 min, then perform dry granulation. Set the oil pressure to 0-7 MPa, the conveying speed to 20-40 rpm, and the pressure roller speed to 15 rpm. Use an 18-mesh sieve and a granulation speed of 50-80 rpm.

[0016] (3) After dry granulation, add the remaining 0.5% magnesium stearate to the granules, mix them together in a mixer, and then compress them into tablets.

[0017] Example 2 prescription Sevelamer carbonate 70% Calcium carbonate 5% Corn starch (added internally) 9% Microcrystalline cellulose (added internally) 8% Microcrystalline cellulose (added) 7% 1% magnesium stearate Preparation process (1) Take the prescribed amount of corn starch and the prescribed amount of calcium carbonate and microcrystalline cellulose (added internally) for wet granulation. Set the stirring speed to 300 rpm and the shearing speed to 1500 rpm. Add purified water at 20% of the total weight of the materials. After granulation, the soft material is granulated through a 20-mesh sieve and set aside as granules 1.

[0018] (2) Take sevelamer carbonate, microcrystalline cellulose (added), and the above-mentioned granules 1, mix them in a mixer for 10 min, add 0.5% magnesium stearate and mix for 5 min, then perform dry granulation. Set the oil pressure to 0-7 MPa, the conveying speed to 20-40 rpm, and the pressure roller speed to 15 rpm. Use an 18-mesh sieve and a granulation speed of 50-80 rpm.

[0019] (3) After dry granulation, add the remaining 0.5% magnesium stearate to the granules, mix them together in a mixer, and then compress them into tablets.

[0020] Example 3 prescription Sevelamer carbonate 70% Calcium carbonate 5% Corn starch (added internally) 9% Microcrystalline cellulose (added internally) 8% Microcrystalline cellulose (added) 7% 1% magnesium stearate Preparation process (1) Take the prescribed amount of corn starch and the prescribed amount of calcium carbonate and microcrystalline cellulose (added internally) for wet granulation. Set the stirring speed to 300 rpm and the shearing speed to 1500 rpm. Add purified water at 25% of the total weight of the materials. After granulation, the soft material is granulated through a 20-mesh sieve and set aside as granules 1.

[0021] (2) Take sevelamer carbonate, microcrystalline cellulose (added), and the above-mentioned granules 1, mix them in a mixer for 10 min, add 0.5% magnesium stearate and mix for 5 min, then perform dry granulation. Set the oil pressure to 0-7 MPa, the conveying speed to 20-40 rpm, and the pressure roller speed to 15 rpm. Use an 18-mesh sieve and a granulation speed of 50-80 rpm.

[0022] (3) After dry granulation, add the remaining 0.5% magnesium stearate to the granules, mix them together in a mixer, and then compress them into tablets.

[0023] Example 4 (Control) prescription Sevelamer carbonate 70% Calcium carbonate 5% Corn starch (added internally) 9% Microcrystalline cellulose (added internally) 8% Microcrystalline cellulose (added) 7% 1% magnesium stearate Preparation process (1) Take the prescribed amount of corn starch and the prescribed amount of calcium carbonate and microcrystalline cellulose (added internally) for wet granulation. Set the stirring speed to 300 rpm and the shearing speed to 1500 rpm. Add anhydrous ethanol at 15% of the total weight of the materials. After granulation, the soft material is granulated through a 20-mesh sieve and set aside as granules 1.

[0024] (2) Take sevelamer carbonate, microcrystalline cellulose (added), and the above-mentioned granules 1, mix them in a mixer for 10 min, add 0.5% magnesium stearate and mix for 5 min, then perform dry granulation. Set the oil pressure to 0-7 MPa, the conveying speed to 20-40 rpm, and the pressure roller speed to 15 rpm. Use an 18-mesh sieve and a granulation speed of 50-80 rpm.

[0025] (3) After dry granulation, add the remaining 0.5% magnesium stearate to the granules, mix them together in a mixer, and then compress them into tablets.

[0026] The moisture uniformity of the prepared tablets was investigated using the formulation processes of Examples 1-4 of the present invention. One tablet was taken, ground in a mortar and pestle, and then passed through a 20-mesh sieve. A rapid moisture analyzer was used in automatic mode at 85°C for 2 hours. Ten tablets were measured, and their RSD was calculated to evaluate the moisture uniformity. The results are shown in Table 1. The results show that in Examples 1-3, when the amount of purified water added during wet granulation was 15%-25% of the total weight of the material, the moisture content of the prepared tablets was within the prescribed limits, and the moisture uniformity met the requirements. Example 4 served as a control group, using anhydrous ethanol as a wetting agent. The moisture content of its tablets met the prescribed limits, but the RSD was larger, indicating poor moisture uniformity.

[0027] Table 1 Results of the moisture content study The hygroscopicity of the prepared tablets was investigated using the formulation process of Examples 1-4 of the present invention. The results are shown in Table 2.

[0028] Table 2. Results of the hygroscopicity test Five tablets were taken, their net weight was measured, and they were placed in a 92.5% RH environment for 24 hours to observe the moisture absorption and weight gain. The experimental results showed that in Examples 1-3, when the amount of purified water added during wet granulation was 15%-25% of the total material weight, there was no significant difference in the moisture absorption and weight gain of the resulting tablets. Example 4, as a control group, used anhydrous ethanol as a wetting agent, and its tablets showed a greater moisture absorption and weight gain, indicating poor stability at 92.5% RH.

[0029] Group 92.5%RH - 24-hour moisture absorption weight gain (%) Example 1 4.2 Example 2 4.5 Example 3 4.1 Example 4 8.8 To further illustrate the advantages of this invention in storage stability compared to the reference formulation, tablets prepared in Examples 1-3 of this invention and the reference formulation were placed under accelerated conditions (40℃-75%RH) for 6 months. The disintegration time, content, soluble oligomers, and loss on drying parameters were investigated, and the results are shown in Table 3. The results show that the disintegration time and loss on drying of the reference formulation increased significantly after 6 months of accelerated storage. However, the tablets prepared with a water content range of 15%-25% in this invention showed no significant change in disintegration time and loss on drying parameters compared to 0% after 6 months of accelerated storage, thus ensuring better storage stability.

[0030] Table 3. Stability Study

Claims

1. A sevelamer carbonate tablet and a method of preparing the same, characterized by The tablet is prepared by wet granulation of calcium carbonate, microcrystalline cellulose (internal), purified water, and dry granulation of the prepared granules with sevelamer carbonate, microcrystalline cellulose (external) and magnesium stearate.

2. The sevelamer carbonate tablet according to claim 1, wherein Sevelamer carbonate accounts for 70% of the tablet, calcium carbonate accounts for 5%, corn starch accounts for 9%, microcrystalline cellulose accounts for 15%, and magnesium stearate accounts for 1%.

3. The sevelamer carbonate tablet according to claim 1, wherein The model of microcrystalline cellulose is ZW-112.

4. The sevelamer carbonate tablet according to claim 1, wherein The internal microcrystalline cellulose accounts for 8%, and the external microcrystalline cellulose accounts for 7%.

5. The method of claim 1, wherein the method further comprises the step of: The amount of purified water added during wet granulation is 15%-25% of the total weight of the material. ​

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