Sevelamer carbonate coated tablets and methods of making the same

Abstract

The present application relates to the technical field of preparation of sevelamer carbonate tablets, in particular to a sevelamer carbonate coated tablet and a preparation method thereof. The preparation method of the sevelamer carbonate coated tablet comprises: homogenizing sevelamer carbonate raw materials, a filler and a solvent, then performing spray drying, and then mixing the disintegrating agent and the lubricant uniformly, and then performing tabletting. The hardness of the tablet prepared by the preparation method is above 500N, the surface of the tablet is smooth, the tablet can be normally coated without using a special coating process, and the coated tablet prepared meets the requirements of disintegration time and stability.

Description

Technical Field

[0001] This invention relates to the field of preparation technology of sevelamer carbonate tablets, and more specifically, to sevelamer carbonate coated tablets and their preparation method. Background Technology

[0002] Sevelamer carbonate is a highly cross-linked polymer with high elasticity but poor plasticity. It is hygroscopic, has poor flowability, and is difficult to compress into tablets. Existing technologies offer numerous methods for preparing sevelamer carbonate tablets, but all have certain problems. For example, the preparation process described in patent WO2014071757A1 is as follows:

[0003]

[0004] The hardness of the raw sheet prepared by this method does not exceed 300N. The preparation process of patent CN102895204B is as follows:

[0005]

[0006] The hardness of the raw sheet prepared by this method exceeds 250 N. The preparation process of CN107397734A is as follows:

[0007]

[0008] The hardness of the raw film produced by this technology does not exceed 300N. When the hardness of the raw film is below 300N, it is prone to powdering and surface roughness during subsequent coating steps. Therefore, how to increase the hardness of the raw film so that it can be coated normally without the need for a special coating process, and how to simultaneously meet the requirements of disintegration time and stability of the coated film while increasing the hardness of the raw film for normal coating, are urgent technical problems that need to be solved.

[0009] In view of this, the present invention is proposed. Summary of the Invention

[0010] The purpose of this invention is to provide sevelamer carbonate-coated tablets and a method for preparing the same. The tablets prepared by the method provided in this invention have a hardness of over 500 N, a smooth surface, and can be normally coated without requiring a special coating process. Furthermore, the prepared coated tablets meet requirements for disintegration time and stability.

[0011] This invention is implemented as follows:

[0012] In a first aspect, the present invention provides a method for preparing sevelamer carbonate-coated tablets, comprising: homogenizing sevelamer carbonate raw material, filler and solvent and spray drying them, then mixing them evenly with disintegrant and lubricant, and then compressing them into tablets.

[0013] In an optional embodiment, the conditions for spray drying include: an inlet air temperature of 110-130°C;

[0014] Preferably, the conditions for spray drying also include: an air supply volume of 9-10 m³ / h. 3 / min, spray speed is 280-320rpm.

[0015] In an optional embodiment, the mass of the disintegrant is 0.05-2.0% of the total mass of the sevelam carbonate raw material, the filler, the disintegrant, and the lubricant, preferably 1%.

[0016] Preferably, the mass of the lubricant is 0.1-2.0% of the total mass of the sevelam carbonate raw material, the filler, the disintegrant, and the lubricant, and more preferably 0.3%.

[0017] Preferably, the mass of the filler is 16-18.5% of the total mass of the sevelam carbonate raw material, the filler, the disintegrant, and the lubricant;

[0018] Preferably, the mass of the sevelamer carbonate raw material is 80-83% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant, and the lubricant.

[0019] In an optional embodiment, the filler includes at least one of microcrystalline cellulose, β-cyclodextrin, and starch.

[0020] In an optional embodiment, the disintegrant includes at least one of sodium carbonate, sodium bicarbonate, and silicon dioxide.

[0021] In an optional embodiment, the lubricant is an external lubricant;

[0022] Preferably, the lubricant comprises stearic acid-based substances;

[0023] Preferably, the lubricant comprises at least one of zinc stearate, stearic acid, and sodium stearate fumarate; most preferably, zinc stearate.

[0024] In an optional embodiment, the D of the sevelam carbonate feedstock 0.9 No larger than 150 micrometers, D 0.5 No larger than 80 micrometers, D 0.01 Not less than 3 micrometers.

[0025] In an optional embodiment, the preparation method further includes: coating after tableting.

[0026] In an optional embodiment, the preparation method further includes: after spray drying, and before mixing with the disintegrant and the lubricant, sieving the mixed powder obtained by spray drying.

[0027] Secondly, the present invention provides a sevelamer carbonate-coated tablet, which is prepared by the preparation method of sevelamer carbonate-coated tablets described in any of the foregoing embodiments.

[0028] The present invention has the following beneficial effects: The preparation method provided in the embodiments of the present invention, by first homogenizing sevelamer carbonate raw material, filler, and solvent, followed by spray drying, and then mixing with disintegrant and lubricant, can effectively improve the properties of the active pharmaceutical ingredient. Furthermore, the bulk density and tap density of the intermediate particles are larger than those obtained by wet granulation, and the flowability is significantly improved. Simultaneously, the tablets obtained by compression have a hardness of over 500N, a smooth surface, and can be normally coated without the need for special coating methods. Moreover, the coated tablets have a short disintegration time and high stability. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0030] This invention provides a method for preparing sevelamer carbonate-coated tablets, the specific process flow of which is shown below:

[0031]

[0032] The specific process includes:

[0033] Sevelamer carbonate raw material and filler are added to a solvent (e.g., purified water) and homogenized to form a suspension. The homogenized suspension is then spray-dried to form a mixed powder.

[0034] It should be noted that the homogenization conditions can be existing conventional homogenization conditions. The conditions provided in the embodiments of this invention are merely examples and do not imply that only the homogenization conditions provided in the embodiments of this invention can be used. For example, the homogenization time is 25-35 minutes, and the homogenizer speed is 1000-5000 rpm.

[0035] The conditions for spray drying include: an inlet air temperature of 110-130℃; for example, any value between 110℃, 115℃, 120℃, 125℃, and 130℃. The air supply volume is 9-10 m³ / h. 3 / min, for example, 9m 3 / min, 9.1m 3 / min, 9.2m 3 / min, 9.3m 3 / min, 9.4m 3 / min, 9.5m 3 / min, 9.6m 3 / min, 9.7m 3 / min, 9.8m 3 / min, 9.9m 3 / min and 10m 3 / min etc. 9-10m 3 Any value between / min. The spray speed is 280-320rpm, such as 280rpm, 285rpm, 290rpm, 295rpm, 300rpm, 305rpm, 310rpm, 315rpm, and 320rpm.

[0036] Furthermore, the D of the said sevelam carbonate raw material 0.9 No larger than 150 micrometers, D 0.5 No larger than 80 micrometers, D 0.01 The particle size is not less than 3 micrometers. The filler includes at least one of microcrystalline cellulose, β-cyclodextrin, and starch. Selecting the above filler and sevelamer carbonate raw material is beneficial to improving the performance of the sevelamer carbonate-coated tablets prepared subsequently.

[0037] The sprayed powder mixture is sieved through a screen (e.g., 20 mesh). The sieved material, disintegrant, and lubricant are then added to a mixer and mixed thoroughly to obtain a final mixture. Next, the final mixture is directly compressed into tablets at a specification of 800 mg / tablet.

[0038] Further, the disintegrant includes at least one of sodium carbonate, sodium bicarbonate, and silicon dioxide. The lubricant is an external lubricant; the lubricant includes stearic acid substances; for example, it includes at least one of zinc stearate, stearic acid, and sodium stearate fumarate; most preferably, zinc stearate.

[0039] Further, the mass of the disintegrant is 0.05-2.0% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant, and the lubricant, preferably 1%; the mass of the lubricant is 0.1-2.0% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant, and the lubricant, preferably 0.3%; the mass of the filler is 16-18.5% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant, and the lubricant; and the mass of the sevelamer carbonate raw material is 80-83% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant, and the lubricant.

[0040] Using the above-mentioned disintegrants and lubricants, along with the above-mentioned dosage limits, is beneficial to improving the performance of the sevelamer carbonate-coated tablets prepared subsequently.

[0041] The inventors discovered that when the hardness of the uncoated tablets is below 300N, the tablets are prone to powdering and surface roughness during subsequent coating steps. However, when the hardness of the uncoated tablets is above 500N, the surface is smooth and can be coated normally without requiring a special coating degree. In this invention, sevelamer carbonate raw material is first mixed with a filler and spray-dried, and then mixed with a disintegrant and lubricant. This results in uncoated tablets with a hardness higher than 500N, a smooth surface suitable for normal coating, and a short disintegration time after coating.

[0042] Next, the uncoated tablets are coated using existing, conventional, and known coating methods. The coating steps provided in this embodiment are merely examples. Specifically, a common gastric-soluble coating premix is ​​used as the coating material. The coating material is suspended uniformly in purified water to prepare a coating solution with a solid content of 10%. The coating temperature is controlled at 45-55°C, and the coating weight gain range is 2-4%.

[0043] This invention also provides a sevelamer carbonate-coated tablet, which is prepared by the method for preparing sevelamer carbonate-coated tablets described in any of the foregoing embodiments.

[0044] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0045] Examples 1-3

[0046] Examples 1-3 provide a method for preparing sevelamer carbonate tablets. The operation steps of each example are basically the same, the difference being that the amount of each substance is different. The amount is shown in Table 1. The specific process is as follows:

[0047] Sevelamer carbonate and microcrystalline cellulose, as recorded in Table 1, were added to 5L of purified water and homogenized for 30 minutes at 4000 rpm. The homogenized suspension was then spray-dried, with the inlet air temperature set to 120℃ and the air volume to 9.5 m³ / h. 3 The spray speed was 300 rpm. The resulting mixed powder was passed through a 20-mesh sieve. Then, the sieved material, along with the disintegrant sodium bicarbonate and lubricant zinc stearate as recorded in Table 1, were added to the mixer and mixed for 5 minutes to obtain the final mixture. The final mixture was directly compressed into tablets at a specification of 800 mg / tablet. The tableting process and tablet hardness were recorded and tested (see Table 1).

[0048] Table 1. Dosage of Examples 1-3 and Comparative Examples 1-2

[0049]

[0050] As shown in Table 1, when the amount of filler is changed, i.e. the amount of microcrystalline cellulose is not within the range of the embodiments of the present invention, the hardness of the unflakes is less than 500N, and even if a disintegrant is added, the disintegration time is prolonged. However, the unflakes obtained by using the ratio provided in the embodiments of the present invention not only have a hardness higher than 500N, but also significantly shorten the disintegration time.

[0051] Examples 4-6

[0052] Examples 4-6 provide a method for preparing sevelamer carbonate tablets. The operation steps of each example are basically the same, the difference being that the inlet air temperature of the spray dryer is different. See Table 2 for details. The specific process is as follows:

[0053] Sevelamer carbonate and microcrystalline cellulose (Table 2 dosage) were added to 5L of purified water and homogenized for 30 minutes at 4000 rpm using a homogenizer. The homogenized suspension was then spray-dried, with the spray parameters set to an airflow rate of 9.5 m³ / h. 3 The spray speed was 300 rpm. The powder obtained after spraying was passed through a 20-mesh sieve. Then, the sieved material, along with the prescribed amounts of disintegrant sodium bicarbonate and lubricant zinc stearate, were added to a mixer and mixed for 5 minutes to obtain a total mixture. The bulk density, tapped density, and angle of repose of the total mixture were tested. The total mixture was then directly compressed into tablets at a specification of 800 mg / tablet. The tableting results were recorded, and the hardness and content uniformity of the unprocessed tablets were tested. See Table 3.

[0054] Table 2. Prescriptions and conditions for Examples 4-6

[0055]

[0056]

[0057] Table 3 Content Uniformity Data

[0058]

[0059] Comparative Example 3 and Comparative Example 4

[0060] Comparative Examples 3 and 4 also provide methods for preparing sevelamer carbonate tablets. The amounts of each substance are shown in Table 4, and the specific procedures are as follows:

[0061] Sevelamer carbonate and microcrystalline cellulose were added to a wet granulator according to the dosages in Table 4 and premixed for 5 minutes. Then, the granulation cutter was turned on, and purified water of the prescribed amount was added for granulation for 3 minutes. The granulated particles were then wet-sized using a 20-mesh vibrating granulator. The sized wet particles were added to a mixer, and sodium bicarbonate and zinc stearate were added as disintegrants according to Table 4. The mixing time was 5 minutes. The bulk density, tap density, and angle of repose of the total mixed particles were tested. The total mixed particles were then compressed into tablets at a specification of 800 mg / tablet. The tableting results were recorded, and the hardness of the unprocessed tablets was tested (see Table 4).

[0062] Table 4

[0063]

[0064]

[0065] As shown in Tables 2-4, the mixture obtained by spray drying according to the embodiments of the present invention has a uniform content, and the bulk density and tap density of the particles are greater than those obtained by wet granulation. Furthermore, the angle of repose is smaller, and the flowability is better. The total moisture content of the spray-dried mixture is in the range of 8-13%, exhibiting good compressibility. All of these particles can be compressed to a hardness of over 500N to meet subsequent coating requirements. In contrast, the intermediate particles obtained by wet granulation have poor compressibility, and the highest hardness of the compressed particles can only reach 305N.

[0066] Example 7

[0067] Example 7 and Comparative Examples 5-7 respectively provide a method for preparing sevelamer carbonate-coated tablets, which are obtained by coating the sevelamer carbonate tablets of Example 5 and Comparative Examples 2-4 respectively, and then obtaining the corresponding sevelamer carbonate-coated tablets. Specifically:

[0068] Take 800g each of the sevelamer carbonate tablets from Example 5 and Comparative Examples 2-4 and coat them. The coating process is as follows:

[0069] 1. Prepare 500g of coating solution with a solid content of 10%. The coating powder material is a common gastric-soluble coating premix. Dissolve or suspend the coating material in purified water slurry evenly and set aside.

[0070] 2. Start the coating machine main unit, turn on the hot air to preheat the pan to 45℃, and the pan rotation speed is 3 rpm. Then place the sevelamin carbonate tablets in the high-efficiency coating machine and continue to preheat for 5 minutes.

[0071] 3. Coating: Increase the speed of the pan to 10 rpm, turn on the spray gun, and spray the prepared coating solution onto the surface of the core. Control the air inlet temperature within the range of 45-55℃, the coating time is 40-60 minutes, and the weight gain is controlled within 2-4%.

[0072] After coating, the obtained sevelamer carbonate-coated tablets were tested. The disintegration time test method followed the method outlined in General Chapter 0921 of the Pharmacopoeia of the People's Republic of China, and the stability test followed the Technical Guidelines for Stability Studies of Chemical Drugs (Active Pharmaceutical Ingredients and Preparations) in the 2015 edition of the Pharmacopoeia. See Tables 5-7 for the test results.

[0073] Table 5. Appearance of Sevelamer Carbonate Coated Flakes

[0074]

[0075] Table 6 Disintegration time of sevelamer carbonate-coated tablets

[0076] Coated sheets Original research tablets Comparative Example 5 Example 7 Comparative Example 6 Comparative Example 7 Disintegration Time 5min 7min 4min 10min 9min

[0077] Table 7. Stability of sevelamer carbonate-coated tablets (accelerated at 40°C)

[0078] Acceleration time 0 days January February March June Comparative Example 5 7min 7min 8min 10min 12min Example 7 4min 4min 5min 8min 10min Comparative Example 6 10min 14min 18min 26min 35min Comparative Example 7 9min 15min 20min 29min 40min

[0079] Table 5 shows that the results after coating indicate that sevelamer carbonate tablets with a hardness above 500 N can be successfully coated. Coating sevelamer carbonate tablets with a hardness below 500 N may result in a rough surface and edge damage.

[0080] As shown in Table 6, the disintegration times of the sevelamer carbonate tablets of Comparative Examples 3 and 4, corresponding to the sevelamer carbonate-coated tablets of Comparative Examples 5 and 6, were significantly slower than those of the original tablets. The disintegration time of the sevelamer carbonate tablets of Comparative Example 2, corresponding to the sevelamer carbonate-coated tablets of Comparative Example 5, was slightly slower than that of the original tablets. The disintegration time of the sevelamer carbonate tablets of Example 5, corresponding to the sevelamer carbonate-coated tablets of Example 7, was similar to that of the original tablets. This indicates that the uncoated tablets obtained by spray drying process have better disintegration effects, and the disintegration effect of the coated tablets obtained after adding disintegrants is similar to that of the original tablets.

[0081] Further analysis of Table 7 shows that the sevelamin carbonate tablets of Comparative Example 2 and Example 5, respectively, exhibit rapid disintegration within 6 months, while the disintegration time of the tablets coated with Formulations 9 and 10 is significantly slower within 6 months. This indicates that the tablets prepared using the processes of Formulations 4 and 7 have good stability. Spray drying of the mixture helps reduce tablet disintegration time, and the addition of a disintegrant further accelerates disintegration, achieving a disintegration time similar to the original drug, and the resulting coated tablets exhibit good stability.

[0082] In summary, the embodiments of this invention, by first homogenizing the sevelamer carbonate raw material and the filler in water to form a suspension and then spray-drying it, ensure that the spray-dried mixture binds tightly with the filler, effectively improving the properties of the active pharmaceutical ingredient and enhancing the flowability and compressibility of the intermediate material, which is beneficial for subsequent tableting processes. Furthermore, the uncoated tablets obtained through the above operation can achieve a hardness of over 500N, allowing for direct conventional coating without the need for special coating methods. The coated tablets also exhibit short disintegration times and good stability.

[0083] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method of preparing a sevelamer carbonate coated tablet, characterized in that, The preparation method comprises the following steps: homogenizing the sevelamer carbonate raw material, the filler and the solvent, then performing spray drying, and then mixing the disintegrant and the lubricant, and then performing tabletting; wherein the mass of the disintegrant is 0.05-2.0% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant and the lubricant; the mass of the lubricant is 0.1-2.0% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant and the lubricant; the mass of the filler is 16-18.5% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant and the lubricant; the mass of the sevelamer carbonate raw material is 80-83% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant and the lubricant; the spray drying conditions comprise: the inlet air temperature is 110-130℃; the filler is microcrystalline cellulose.

2. The method of claim 1, wherein the sevelamer carbonate coated tablet is prepared by, The conditions for spray drying also include: air supply amount is 9-10 m 3 / min, spray rotation speed is 280-320 rpm.

3. The method of preparing sevelamer carbonate coated tablets according to claim 1 or 2, characterized in that, The disintegrant comprises at least one of sodium carbonate, sodium bicarbonate and silicon dioxide.

4. The method of preparing sevelamer carbonate coated tablets according to claim 1 or 2, characterized in that, The lubricant is an external lubricant.

5. The method of preparing sevelamer carbonate coated tablets according to claim 1 or 2, characterized in that, The lubricant comprises a stearic acid substance.

6. The method of preparing sevelamer carbonate coated tablets according to claim 1 or 2, characterized in that, The lubricant comprises at least one of zinc stearate, stearic acid and sodium stearyl fumarate.

7. The method of claim 1 or 2, wherein the method is characterized by, The lubricant is zinc stearate.

8. The method of claim 1 or 2, wherein the method is characterized by, D90 of the sevelamer carbonate raw material is not greater than 150 microns 0.9 not greater than 150 microns, D90 0.5 not greater than 80 microns, D90 0.01 not less than 3 microns.

9. The method of claim 1, wherein the sevelamer carbonate coated tablet is prepared by, The preparation method further comprises: performing coating after tabletting.

10. The method of claim 1, wherein the sevelamer carbonate coated tablet is prepared by, The preparation method further comprises: sieving the mixed powder obtained by spray drying before mixing with the disintegrant and the lubricant.

11. A sevelamer carbonate coated tablet, characterized in that, The coated tablet is prepared by the preparation method of the sevelamer carbonate coated tablet according to any one of claims 1-10. The preparation method comprises the following steps: homogenizing the sevelamer carbonate raw material, the filler and the solvent, then performing spray drying, and then mixing the disintegrant and the lubricant, and then performing tabletting; wherein the mass of the disintegrant is 0.05-2.0% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant and the lubricant; the mass of the lubricant is 0.1-2.0% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant and the lubricant; the mass of the filler is 16-18.5% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant and the lubricant; the mass of the sevelamer carbonate raw material is 80-83% of the total mass of the sevelamer carbonate raw material, the filler, the disintegrant and the lubricant; the spray drying conditions comprise: the inlet air temperature is 110-130℃; the filler is microcrystalline cellulose. The disintegrant comprises at least one of sodium carbonate, sodium bicarbonate and silicon dioxide. The lubricant is an external lubricant. The lubricant comprises a stearic acid substance. The lubricant comprises at least one of zinc stearate, stearic acid and sodium stearyl fumarate. The lubricant is zinc stearate. The preparation method further comprises: performing coating after tabletting. The preparation method further comprises: sieving the mixed powder obtained by spray drying before mixing with the disintegrant and the lubricant. The coated tablet is prepared by the preparation method of the sevelamer carbonate coated tablet according to any one of claims 1-10.

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