Persistent release fluorocalcitriol tablet and preparation method thereof

Abstract

The invention provides a sustained-release fluorocalcitriol tablet and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, the preparation raw materials comprise a sustained-release skeleton layer prepared from a fluorocalcitriol-containing drug core particle and a controlled-release film coating solution containing a methacrylate copolymer, the preparation method comprises the following steps: preparing the medicine core, preparing the controlled-release film coating solution and coating, preparing the controlled-release skeleton layer, and drying and packaging.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a sustained-release fluorocalcitriol tablet and a preparation method thereof. Background Art

[0002] With the rapid development of medical technology, treatment options for bone diseases are constantly being innovated. Among them, calcitriol, as the most active form of vitamin D3, plays a vital role in regulating calcium and phosphorus metabolism and promoting bone health. However, traditional non-sustained release calcitriol preparations face a series of challenges and limitations in practical applications, which not only affect the therapeutic effect of the drug, but also limit the patient's medication experience and compliance. Traditional non-sustained release calcitriol preparations are mostly immediate release. The drug dissolves quickly and is released into the blood after oral administration, causing the blood drug concentration to rise rapidly in a short period of time and then fall rapidly. This drastic fluctuation is not only not conducive to maintaining stable drug efficacy, but may also cause side effects such as hypercalcemia and hyperphosphatemia due to excessively high peak blood drug concentrations. In order to maintain effective blood drug concentrations, patients need to take immediate release calcitriol preparations frequently. This not only increases the patient's medication burden, but may also lead to missed doses due to forgetfulness or inconvenience, thus affecting the treatment effect. Different patients have different physiological states, metabolic rates and drug sensitivities, resulting in different responses to immediate-release fluorocalcitriol preparations. Such individual differences make it complicated and difficult to adjust the drug dosage, making it difficult to achieve the best therapeutic effect. Immediate-release fluorocalcitriol preparations may be affected by factors such as light and temperature during storage and transportation, resulting in drug degradation or failure. This not only reduces the effectiveness of the drug, but also may increase the risk of medication for patients. In addition, with the increasing aging of the population and the rising incidence of bone diseases, the market demand for sustained-release fluorocalcitriol preparations is becoming increasingly urgent. Both patients and doctors are eager for a drug preparation that can reduce the frequency of administration, improve the therapeutic effect, and reduce the risk of side effects. In addition, with the continuous advancement of medical technology and the patient's pursuit of quality of life, the personalization, intelligence and convenience of sustained-release preparations have also become a new market trend. In summary, traditional non-sustained-release fluorocalcitriol preparations have many limitations and challenges in application, and the development of sustained-release preparations has become an important way to solve these problems. Therefore, a new sustained-release fluorocalcitriol tablet and its preparation method are urgently needed in the market. Summary of the invention

[0003] The present invention provides a sustained-release fluorocalcitriol tablet and a preparation method thereof, which are used to solve the problems raised in the above-mentioned background technology.

[0004] In order to solve the above technical problems, the present invention discloses a sustained-release fluorocalcitriol tablet and a preparation method thereof. The sustained-release fluorocalcitriol tablet comprises a sustained-release skeleton layer prepared from drug core particles containing fluorocalcitriol and a controlled-release membrane coating solution containing a methacrylate copolymer.

[0005] Furthermore, the raw materials for preparing the drug core particles containing fluorocalciferol include fluorocalcitriol, microcrystalline cellulose, lactose, mannitol, povidone K30, hydroxypropyl methylcellulose, nano-silicon dioxide, tert-butylhydroquinone, vitamin E acetate and purified water.

[0006] Furthermore, the raw materials for preparing the drug core particles containing fluorocalciferol include, by weight, 0.03-0.032 parts of fluorocalcitriol, 30-35 parts of microcrystalline cellulose, 15-20 parts of lactose, 5-6 parts of mannitol, 4-5 parts of povidone K30, 2-3 parts of hydroxypropyl methylcellulose, 2-3 parts of nano silicon dioxide, 0.02-0.03 parts of tert-butylhydroquinone and 0.02-0.04 parts of vitamin E acetate and 20-25 parts of purified water.

[0007] Furthermore, the raw materials for preparing the controlled-release film coating solution containing methacrylate copolymer include methacrylate copolymer, cross-linked polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl methylcellulose, PEG 4000, sucrose, sodium chloride, triacetin, polyvinyl alcohol, carnauba wax and ethanol.

[0008] Furthermore, the raw materials for preparing the controlled-release membrane coating solution containing methacrylate copolymer include, by weight, 30-35 parts of methacrylate copolymer, 2-3 parts of cross-linked polyvinyl pyrrolidone, 3-5 parts of ethyl cellulose, 2-5 parts of hydroxypropyl methylcellulose, 2-3 parts of PEG 4000, 1-2 parts of sucrose, 0.4-0.5 parts of sodium chloride, 1.5-2 parts of triacetin, 1-2 parts of polyvinyl alcohol, 1-2 parts of carnauba wax and 15-20 parts of ethanol.

[0009] Furthermore, the raw materials for preparing the sustained-release skeleton layer prepared by using the drug core particles containing fluorocalciferol and the controlled-release membrane coating solution containing a methacrylate copolymer also include a polyvinyl acetate-povidone mixture and magnesium stearate.

[0010] Furthermore, the raw materials for preparing the sustained-release skeleton layer prepared by using the drug core particles containing fluorocalciferol and the controlled-release membrane coating solution containing a methacrylate copolymer include, by weight, 0.3-0.4 parts of drug core particles, 8-10 parts of a polyvinyl acetate-povidone mixture, 2-3 parts of magnesium stearate, 3-4 parts of hydroxypropyl methylcellulose, 8-10 parts of pure water and 0.5-0.6 parts of coated drug core particles.

[0011] Furthermore, the preparation method includes preparing the drug core, preparing the controlled release membrane coating solution and coating, preparing the sustained release skeleton layer and dry packaging.

[0012] Furthermore, when preparing the drug core, fluorocalcitriol is mixed with microcrystalline cellulose, lactose, mannitol, povidone K30, hypromellose, nano-silica pore-forming agent, tert-butylhydroquinone, vitamin E acetate and purified water, and prepared into granules by wet granulation technology. The wet granules are placed in a drying oven and dried at 50-60° C. The dried granules are granulated by a granulator to obtain uniform drug core particles.

[0013] Furthermore, when preparing the controlled release film coating and coating, Eudragit RS methacrylate copolymer, cross-linked polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl methylcellulose, PEG 4000, sucrose, sodium chloride, triacetin, polyvinyl alcohol, carnauba wax and ethanol are mixed and stirred to obtain a controlled release film coating solution, the drug core particles obtained in step 1 are placed in a fluidized bed, the air flow is turned on to suspend the particles, and the coating solution is evenly sprayed on the surface of the particles using a spray device to form a controlled release film layer. During the spraying process, the spray rate, temperature and coating solution concentration need to be controlled to ensure the uniformity and thickness of the film layer. After the coating is completed, the particles are continued to be dried in the fluidized bed until the solvent is completely volatilized to obtain coated drug core particles; Preferably, when preparing the sustained-release skeleton layer, the drug core particles, the polyvinyl acetate-povidone mixture, magnesium stearate, hypromellose and pure water are mixed and stirred, and evenly sprayed on the surface of the coated drug core particles to form a sustained-release skeleton layer through a fluidized bed. During the spraying process, the spraying rate and uniformity need to be controlled to ensure the thickness and uniformity of the skeleton layer; Preferably, during the dry packaging, the prepared tablets are dried to remove the residual solvent, and then 0.6-0.8 parts of magnesium stearate and 0.4-0.6 parts of nano silicon dioxide are added and mixed in a mixer to ensure the smoothness of the tablets during the tableting process and the ease of the finished product. Finally, the mixed particles are pressed into tablets using a tablet press as needed, and packaged to obtain sustained-release fluorocalcitriol tablets.

[0014] Compared with the prior art, the present invention provides a sustained-release fluorocalcitriol tablet and a preparation method thereof, which has the following beneficial effects: The three-layer structure design achieves the sustained and stable release of fluorocalcitriol in the body, prolongs the duration of drug effect and reduces the number of dosing times; the synergistic effect of the controlled-release membrane and the sustained-release skeleton makes the drug release smoother, reduces the fluctuation of blood drug concentration, and improves the bioavailability and therapeutic effect of the drug; reduces the frequency of dosing, improves the convenience and compliance of patients, and is conducive to long-term treatment management; by adjusting the proportion of each component and the preparation process, the stable production and quality control of the product are achieved, the production cost is reduced, and the market competitiveness is improved; tens of microns of sucrose and sodium chloride and high molecular polymer PEG 4000 can optimize the pore structure of the coating layer and the release rate of the drug at a suitable ratio. The particle size of sucrose will affect its contact area with the drug and the pore structure of the coating layer. Generally speaking, a particle size of tens of microns can increase the contact area between sucrose and the drug, which is beneficial to the release of the drug. Avoiding too small a particle size may also cause the coating layer to be too dense, which in turn hinders the release of the drug. Sodium chloride can also be used as an osmotic pressure regulator. The release rate is adjusted by adding appropriate amounts of hydrophobic polymers such as ethyl cellulose (EC) and hydrophilic polymers such as hydroxypropyl methylcellulose (HPMC). The prepared sustained-release fluorocalcitriol tablets have excellent release performance. Using the intelligent feedback system, an integrated electrostatic generator is set during the coating process, and high-precision sensors are installed to monitor and collect the electric field strength, particle suspension density, size and speed of coating droplets, spray rate, temperature and coating liquid concentration in the spray area, and feedback to the control system for dynamic adjustment to achieve more efficient packaging. The SVM model is used to better predict the thickness and uniformity of the film layer, so as to better realize modern control of the coating with the intelligent feedback system and achieve efficient preparation of drugs. DETAILED DESCRIPTION

[0015] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0016] In addition, in the present invention, the descriptions of "first", "second", etc. are only used for descriptive purposes, and do not specifically refer to the order or sequence, nor are they used to limit the present invention. They are only used to distinguish components or operations described with the same technical terms, and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions and technical features between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in the field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0017] Unless otherwise specified, the examples and comparative examples are parallel tests with the same components, component contents, preparation steps and preparation parameters. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are analytical reagents (AR) unless otherwise specified. Parts are parts by weight unless otherwise specified, and the materials are purchased from commercial channels.

[0018] Lactose was 200 mesh, food grade; microcrystalline cellulose was purchased from Shandong Fengtai Biotechnology Co., Ltd., CAS number: 9004-34-6, (C6H10O5) n , n≈220, particle size is generally 20-80 Lm; mannitol was purchased from Shanghai Linchen Pharmaceutical Technology Co., Ltd., PEARLITOL® 25C, ultra-fine grade; povidone K30 was purchased from Xi'an Jinxiang Pharmaceutical Excipients Co., Ltd., CAS: 9003-39-8, nitrogen content is 11.8%; Hydroxypropyl methylcellulose was purchased from Shanghai Linchen Pharmaceutical Technology Co., Ltd., weight average molecular weight is 400000, nominal viscosity is 2700 (mPa·s); nano-silica pore-forming agent was purchased from Biter Pharmaceuticals, purity 99.5%, CAS: 7631-86-9; methacrylate copolymer brand number is Eudragit RS 100 DMF#1242, composed of ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate copolymer (1:2:0.1); cross-linked polyvinyl pyrrolidone was purchased from Shanghai Hongzuo, CAS No.: 25249-54-1, USP grade, molecular weight 111.1418; ethyl cellulose was purchased from Macklin, CAS No.: 9004-57-3, E915394, 80-120mPa.s, ethoxy: 48.5-49.5%; Hydroxypropyl methylcellulose was purchased from Macklin, brand H811093, viscosity: 15mPa.s, methoxy: 28-30%; hydroxypropyl: 7.0-12%; PEG 4000; sucrose is food grade; carnauba wax was purchased from Zhengyi Auxiliary Materials, purity 99.9%, CAS 8015-86-9; polyvinyl acetate-povidone mixture was purchased from BASF, the name is Kollidon ® SR.

[0019] Example 1 Example 2 The difference from Example 1 is that step 1 is to prepare the drug core: 0.032 parts of fluorocalcitriol are mixed with 35 parts of microcrystalline cellulose, 20 parts of lactose, 6 parts of mannitol, 4 parts of povidone K30, 3 parts of hydroxypropyl methylcellulose (binder), 3 parts of nano-silica pore-forming agent, 0.02 parts of tert-butyl hydroquinone (antioxidant) and 0.04 parts of vitamin E acetate and 25 parts of purified water, and granules are prepared by wet granulation technology. The wet granules are placed in a drying oven and dried at 52°C. The dried granules are granulated by a granulator to obtain uniform drug core particles; the other steps are consistent with Example 1.

[0020] Example 3 The difference from Example 1 lies in that in step 2, a controlled release film coating solution is prepared: 30 parts of Eudragit RS methacrylate copolymer (controlled release material), 2 parts of cross-linked polyvinyl pyrrolidone, 3 parts of ethyl cellulose (controlled release agent), 2 parts of hydroxypropyl methylcellulose, 2 parts of PEG 4000 (pore former), 1 part of sucrose, 0.4 parts of sodium chloride, 1.5 parts of triacetin (plasticizer for improving the flexibility and adhesion of the coating layer), 1 part of polyvinyl alcohol (film-forming agent), 1 part of carnauba wax and 15 parts of ethanol are mixed and stirred to obtain a controlled release film coating solution; the other steps are the same as in Example 1.

[0021] Example 4 The difference from Example 1 is that step 3 is to prepare a sustained-release skeleton layer: 0.3 parts of drug core particles, 8 parts of polyvinyl acetate-povidone mixture, 2 parts of magnesium stearate (anti-adherent), 3 parts of hydroxypropyl methylcellulose and 8 parts of pure water are mixed and stirred, and evenly sprayed on the surface of 0.6 parts of coated drug core particles to form a sustained-release skeleton layer through a fluidized bed. During the spraying process, the spraying rate and uniformity need to be controlled to ensure the thickness and uniformity of the skeleton layer; the other steps are consistent with Example 1.

[0022] Example 5 The difference from Example 1 is that step 4 is drying and packaging: the prepared tablets are dried to remove the residual solvent, and then 0.6 parts of magnesium stearate (as a lubricant) and 0.4 parts of nano silicon dioxide (as an anti-adhesive agent) are added and mixed in a mixer to ensure the smoothness of the tablets during the tableting process and the ease of the finished product. Finally, the mixed particles are pressed into tablets using a tablet press as needed, and packaged to obtain sustained-release fluorocalcitriol tablets; the other steps are consistent with Example 1.

[0023] Example 6 During the coating process, an electrostatic generator is integrated into the spray device to make the coating liquid carry an electrostatic charge when it is sprayed. The strength and polarity of the electrostatic charge need to be carefully adjusted according to the particle material and the properties of the coating liquid to promote the adsorption of the coating liquid on the particle surface. High-precision sensors are installed to monitor and collect the electric field strength, particle suspension density, coating droplet size and speed, spray rate, temperature and coating liquid concentration in the spray area. These data are fed back to the control system in real time to dynamically adjust the output of the electrostatic generator and the parameters of the spray device, turn on the airflow, the flow rate is 2.5m / s, keep the particles suspended, and start the spray device for electrostatic spraying. Since the coating liquid carries static electricity, it will more accurately adsorb to the surface of particles with opposite charges, achieving a more uniform and dense coating coverage; the intelligent feedback system uses the PID (proportional coefficient Kp=2.0, integral coefficient Ki=0.5, differential coefficient Kd=0.1) control algorithm to automatically adjust the airflow based on the monitoring data to maintain the stable suspension state of the particles, and automatically adjust the spray rate, temperature and coating liquid concentration, as well as the output of the electrostatic generator to ensure the uniformity and target thickness of the film layer. For example, when it is detected that the coating is too thick in a certain area, the system will reduce the spray rate in that area; after the coating is completed, the particles continue to be dried in the fluidized bed, and hot air or vacuum drying technology is used to accelerate the evaporation of the solvent. When using hot air drying technology, the temperature is set to 50°C, the wind speed is 1.5m / s, and the duration is 2 hours to accelerate the evaporation of the solvent. At this time, the intelligent feedback system continues to monitor the temperature and humidity of the particles to ensure that the drying process does not damage the film structure or cause particle agglomeration. Curing stage: At the end of the drying stage, a short heating or UV irradiation step is introduced to promote the chemical curing of the coating layer and enhance the stability and durability of the film layer.

[0024] Example 7 The sensor collects the following data in the spray area: spray rate range is 1-10mL / min, temperature range is 40-60°C, coating solution concentration range is 10%-30%, and film thickness (unit: μm) and uniformity (expressed as standard deviation, unit: μm) are measured under each condition. Spray rate (R), temperature (T), coating solution concentration (C) are selected as input features (independent variables), and film thickness (H) and uniformity (σ) are selected as output targets (dependent variables). A support vector machine (SVM) prediction model is trained based on the collected data using the support vector machine (SVM) algorithm. The real-time monitoring data (parameters such as electric field strength (unit: kV / cm), particle suspension density (unit: g / L), coating droplet size (unit: μm) and speed (unit: m / s) are input into the trained SVM model to predict the film thickness and uniformity that may be obtained under the current spray rate, temperature and coating solution concentration) during the electrostatic spraying process. According to the prediction results, if the film thickness or uniformity does not meet the preset standards (for example, the target film thickness is 50 ± 5 μm, and the uniformity standard deviation is less than 5 μm), the spray rate, temperature and coating solution concentration are adjusted using the following formula: ; ; ; in , , is the adjustment coefficient ( , =0.05, =0.02), and are the target film thickness and uniformity, and They are used to predict film thickness and uniformity, respectively.

[0025] Repeat the above prediction and adjustment steps for iterative adjustment until the predicted film thickness and uniformity meet the preset standards.

[0026] Comparative Example 1 The difference from Implementation 1 is that step 3 of preparing the sustained-release matrix layer is omitted, and step 4 of drying and packaging is directly performed using an equal weight portion (0.9 portion) of the coated drug core particles. The other steps are consistent with Example 1.

[0027] Comparative Example 2 The difference from Implementation 1 is that the vitamin E acetate in the middle weight portion in step 1 is missing, and the other steps are consistent with Example 1.

[0028] Comparative Example 3 The difference from Implementation 1 is that the nano-silicon dioxide in the middle weight portion in step 1 is missing, and the other steps are consistent with Example 1.

[0029] Comparative Example 4 The difference from Implementation 1 is that the cross-linked polyvinyl pyrrolidone in step 2 is missing in equal parts by weight, and the other steps are consistent with Implementation 1.

[0030] Comparative Example 5 The difference from Implementation 1 is the lack of sodium chloride in the middle weight portion in step 2, and the other steps are consistent with Example 1.

[0031] Comparative Example 6 The difference from Implementation 1 is that the carnauba wax in the middle weight portion in step 2 is missing, and the other steps are consistent with Example 1.

[0032] Comparative Example 7 The difference from Implementation 1 is that the nano-silicon dioxide in step 4 is missing in weight portion, and the other steps are consistent with Example 1.

[0033] Performance Testing 1. Accelerated test The tablets prepared in Example 1 and the comparative example were placed in an accelerated stability test chamber under high temperature (40°C), light (4500±500Lx), and low temperature (-18°C) conditions. Samples were taken on the 0th and 15th days, respectively, and the various indicators of the stability test were tested. The results are shown in Table 1.

[0034] Table 1

[0035] 2. Stability test The tablets prepared in Example 1 and the comparative example were placed at 40°C and RH75%, and samples were taken at the 0th, 1st and 3rd month, respectively, to test various indicators of the stability test. The results are shown in Table 2.

[0036] Table 2

[0037] It can be seen from this that Example 1 has a stable controlled-release membrane and sustained-release skeleton structure, and can achieve a sustained and stable release of fluorocalcitriol in vivo.

[0038] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. If these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A sustained-release fluorocalcitriol tablet, the preparation raw materials comprising a sustained-release skeleton layer prepared from drug core particles containing fluorocalcitriol and a controlled-release membrane coating solution containing a methacrylate copolymer.

2. The sustained-release fluorocalcitriol tablet according to claim 1, characterized in that: The raw materials for preparing the fluorocalcitriol-containing drug core particles include fluorocalcitriol, microcrystalline cellulose, lactose, mannitol, povidone K30, hydroxypropyl methylcellulose, nano silicon dioxide, tert-butylhydroquinone, vitamin E acetate and purified water.

3. The sustained-release fluorocalcitriol tablet according to claim 1 or 2, characterized in that: The raw materials for preparing the drug core particles containing fluorocalciferol include, by weight, 0.03-0.032 parts of fluorocalcitriol, 30-35 parts of microcrystalline cellulose, 15-20 parts of lactose, 5-6 parts of mannitol, 4-5 parts of povidone K30, 2-3 parts of hydroxypropyl methylcellulose, 2-3 parts of nano silicon dioxide, 0.02-0.03 parts of tert-butylhydroquinone, 0.02-0.04 parts of vitamin E acetate and 20-25 parts of purified water.

4. The sustained-release fluorocalcitriol tablet according to claim 1, characterized in that: The raw materials for preparing the controlled-release film coating solution containing methacrylate copolymer include methacrylate copolymer, cross-linked polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl methylcellulose, PEG 4000, sucrose, sodium chloride, triacetin, polyvinyl alcohol, carnauba wax and ethanol.

5. The sustained-release fluorocalcitriol tablet according to claim 1 or 4, characterized in that: The raw materials for preparing the controlled-release film coating solution containing methacrylate copolymer include, by weight, 30-35 parts of methacrylate copolymer, 2-3 parts of cross-linked polyvinyl pyrrolidone, 3-5 parts of ethyl cellulose, 2-5 parts of hydroxypropyl methylcellulose, 2-3 parts of PEG 4000, 1-2 parts of sucrose, 0.4-0.5 parts of sodium chloride, 1.5-2 parts of triacetin, 1-2 parts of polyvinyl alcohol, 1-2 parts of carnauba wax and 15-20 parts of ethanol.

6. The sustained-release fluorocalcitriol tablet according to claim 1, characterized in that: The raw materials for preparing the sustained-release skeleton layer prepared by using the drug core particles containing fluorocalciferol and the controlled-release membrane coating solution containing a methacrylate copolymer also include a polyvinyl acetate-povidone mixture and magnesium stearate.

7. The sustained-release fluorocalcitriol tablet according to claim 1, characterized in that: The raw materials for preparing the sustained-release skeleton layer prepared by using the drug core particles containing fluorocalciferol and the controlled-release membrane coating solution containing a methacrylate copolymer include, by weight, 0.3-0.4 parts of the drug core particles, 8-10 parts of a polyvinyl acetate-povidone mixture, 2-3 parts of magnesium stearate, 3-4 parts of hypromellose, 8-10 parts of pure water and 0.5-0.6 parts of coated drug core particles.

8. A method for preparing the sustained-release fluorocalcitriol tablets according to any one of claims 1 to 7, characterized in that: The preparation method comprises preparing the drug core, preparing the controlled release film coating liquid and coating, preparing the sustained release skeleton layer and dry packaging.

9. The method for preparing the sustained-release fluorocalcitriol tablet according to claim 8, characterized in that: When preparing the drug core, fluorocalcitriol is mixed with microcrystalline cellulose, lactose, mannitol, povidone K30, hydroxypropyl methylcellulose, nano-silica pore-forming agent, tert-butylhydroquinone, vitamin E acetate and purified water, and granules are prepared by wet granulation technology. The wet granules are placed in a drying oven and dried at 50-60° C. The dried granules are granulated by a granulator to obtain uniform drug core particles.

10. The method for preparing the sustained-release fluorocalcitriol tablet according to claim 8, characterized in that: When preparing the controlled release film coating and coating, Eudragit RS methacrylate copolymer, cross-linked polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl methylcellulose, PEG 4000, sucrose, sodium chloride, triacetin, polyvinyl alcohol, carnauba wax and ethanol are mixed and stirred to obtain a controlled release film coating solution, the drug core particles obtained in step 1 are placed in a fluidized bed, the air flow is turned on to suspend the particles, and the coating solution is evenly sprayed on the surface of the particles using a spray device to form a controlled release film layer. During the spraying process, the spray rate, temperature and coating solution concentration need to be controlled to ensure the uniformity and thickness of the film layer. After the coating is completed, the particles are continued to be dried in the fluidized bed until the solvent is completely volatilized to obtain coated drug core particles; Preferably, when preparing the sustained-release skeleton layer, the drug core particles, the polyvinyl acetate-povidone mixture, magnesium stearate, hypromellose and pure water are mixed and stirred, and evenly sprayed on the surface of the coated drug core particles to form a sustained-release skeleton layer through a fluidized bed. During the spraying process, the spraying rate and uniformity need to be controlled to ensure the thickness and uniformity of the skeleton layer; Preferably, during the dry packaging, the prepared tablets are dried to remove the residual solvent, and then 0.6-0.8 parts of magnesium stearate and 0.4-0.6 parts of nano-silicon dioxide are added and mixed in a mixer to ensure the smoothness of the tablets during the tableting process and the ease of the finished product. Finally, the mixed particles are pressed into tablets using a tablet press as needed, and packaged to obtain sustained-release fluorocalcitriol tablets.

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