Sustained release preparation of rucotinib and preparation method of sustained release preparation

Abstract

According to the sustained release preparation of the reed cotinib and the preparation method of the sustained release preparation, by selecting the specific filling agent, the adhesive, the flow aid and the ratio of all the components as well as parameter conditions in the granulation process, stable release of the sustained release preparation can be ensured, impurity growth in the coating process is inhibited to the greatest extent, and the sustained release preparation of the reed cotinib is prepared. The content uniformity of the sustained release preparation is effectively improved, and the total impurity content and the maximum single impurity content in the product are reduced; meanwhile, the prepared sustained release preparation has the advantages of uniform particle size, good flowability and compression formability, slow dissolution, non-sticking property, uniform medicine content, production time saving and the like, solves the problems of poor sustained release effect and stability, and can solve the adverse effects caused by other preparation methods such as wet granulation and the like. The whole preparation method is simple, has low requirements on production equipment, reduces the production energy consumption, simplifies the production steps, can ensure the product quality, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a sustained-release preparation of ruxolitinib and a preparation method thereof. Background Art

[0002] As a JAK kinase inhibitor, ruxolitinib phosphate has potential anti-tumor and immunomodulatory activities for the treatment of intermediate or high-risk myelofibrosis (MF), including primary myelofibrosis, myelofibrosis after polycythemia vera (PV), and myelofibrosis after essential thrombocythemia (ET). As the first drug for the treatment of myelofibrosis, ruxolitinib phosphate is also the only approved targeted drug for its pathogenesis.

[0003] Currently, ruxolitinib tablets are mainly imported from abroad, and the dosage is 5 mg to 20 mg taken twice a day. More frequent medication increases the undesirable side effects associated with thrombocytopenia and anemia.

[0005] Chinese patent application CN117298055A discloses a ruxolitinib phosphate tablet and its preparation method, the preparation method is premixing of some raw materials and auxiliary materials, wet granulation, drying, granulation and total mixing, tablet compression and packaging. However, there are the following problems: the rapid-release tablets are taken many times, increasing the risk of side effects after taking; the preparation method is cumbersome and has many steps, which not only increases the impurity level, but also has the risk of material loss, resulting in a reduction in the content of active ingredients.

[0006] Chinese patent application CN118217255A discloses a ruxolitinib phosphate tablet and a preparation method thereof, and applies the electrospinning method to the pharmaceutical industry, premixes ruxolitinib phosphate, fillers, adhesives, disintegrants, and flow aids, and remixes the mixture with hydroxypropyl methylcellulose to obtain a mixed solution A; then sodium alginate and carrageenan are mixed to obtain a mixed solution B; finally, the mixed solution A is used as the core layer and the mixed solution B is used as the shell layer for coaxial electrospinning. However, there are the following problems: due to the design configuration of electrospinning machines at home and abroad, it is impossible to obtain filaments or short fibers that can be separated from nanofibers; the current electrospinning technology has low production capacity and cannot meet industrial production.

[0007] Chinese patent application CN113384545A discloses a sustained-release dosage form of ruxolitinib, which is prepared by wet granulation. The following problems exist: the preparation method is complicated and has many steps, which not only increases the level of impurities, but also has the risk of material loss, resulting in a reduction in the content of active ingredients.

[0008] Chinese patent application CN117815195A discloses a JAK inhibitor composition and its preparation process, wherein the pellet core is coated with drugs on the surface of the tartaric acid pellet core to obtain drug-loaded pellets, ethyl cellulose and triethyl citrate are dissolved in ethanol solution for coating to obtain drug-containing sustained-release pellets, mixed, and tableted. Its shortcomings are high impurity levels, poor stability, and the use of ethyl cellulose as a binder only takes 12 hours to fully release, and cannot achieve a longer-lasting release effect.

[0009] The ruxolitinib phosphate tablets disclosed in Chinese patent applications CN117298055A and CN118217255A are both rapid-release tablets, and the active ingredients are completely released only in 1 hour, and cannot achieve a 24-hour steady and slow release; the preparation methods disclosed in Chinese patent applications CN113384545A and CN117815195A have high impurity levels. Therefore, it is necessary to provide a ruxolitinib sustained-release preparation with good sustained-release effect, steady release, low related substances, good stability, and simple preparation method, and a preparation method thereof. Summary of the invention

[0010] The purpose of the present invention is to provide a sustained-release preparation of ruxolitinib based on the prior art.

[0011] Another object of the present invention is to provide a method for preparing the sustained-release preparation of ruxolitinib.

[0012] The technical solution of the present invention is as follows:

[0013] A sustained-release preparation of ruxolitinib, the dosage form of which is a sustained-release micro-pellet, a sustained-release capsule or a sustained-release tablet, wherein the sustained-release micro-pellet is made of a pill core and an isolation layer, wherein the pill core includes an active ingredient ruxolitinib, a filler, a binder and a glidant; and the isolation layer includes a binder and a glidant. The sustained-release micro-pellets are filled into capsules to form sustained-release capsules; or the sustained-release micro-pellets are mixed with excipients and compressed into sustained-release tablets.

[0014] For the sustained-release preparation of ruxolitinib of the present invention, in its preparation process, the drug-containing coating liquid made of the active ingredient ruxolitinib, the binder and the glidant is first used to coat the filler with the drug to prepare the drug-containing pill core, and then the isolation layer coating liquid made of the binder and the glidant is used to coat the obtained drug-containing pill core to prepare the sustained-release micropellets. The obtained sustained-release micropellets can be filled into capsules to prepare sustained-release capsules; or the obtained sustained-release micropellets are mixed with excipients and compressed into sustained-release tablets.

[0015] The sustained-release preparation of ruxolitinib provided by the present invention solves the problems of poor stability, inability to release smoothly and complicated preparation method of the existing ruxolitinib phosphate tablets. In the preparation process of the sustained-release preparation, a filler microcrystalline cellulose pellet core, especially a microcrystalline cellulose pellet core, is used. 100 is used as a pellet carrier, and the type and addition amount of the adhesive hydroxypropyl methylcellulose MK25000PFV are controlled to prepare sustained-release pellets, which can reduce the release rate of ruxolitinib to achieve a smooth release, without adding a sustained-release coating film, and has the advantages of good sustained-release effect, good stability, low content of related substances and high clinical safety. The fluidized bed is used for drug coating. The entire preparation method is simple, has low requirements for production equipment, reduces production energy consumption, simplifies production steps, can ensure product quality and is suitable for large-scale industrial production. At the same time, the use of hydroxypropyl methylcellulose 25000PFV as a coating component can well mask the bitter taste of the drug, which can greatly increase the compliance of patients, especially children, with medication.

[0016] For the present invention, the sustained-release pellets can reduce the release rate of ruxolitinib to achieve a smooth release, without adding a sustained-release coating film, and have the advantages of good sustained-release effect, good stability, low content of related substances, and high clinical safety. For practical needs, the sustained-release pellets can also be further filled into capsules to form sustained-release capsules; or, the sustained-release pellets are mixed with excipients and compressed into sustained-release tablets.

[0017] For the present invention, the filler is microcrystalline cellulose pellets, preferably microcrystalline cellulose pellets. 100. The binder is hydroxypropyl methylcellulose MK25000PFV; the glidant is one or more of silicon dioxide, talc or micro-powdered silica gel, preferably talc; the excipients are diluents and lubricants, wherein the diluent is one or more of microcrystalline cellulose, lactose, mannitol or sorbitol, preferably sorbitol; the lubricant is magnesium stearate and / or sodium stearyl fumarate, preferably magnesium stearate.

[0018] In one embodiment, the sustained-release preparation of ruxolitinib provided by the present invention is in the form of sustained-release pellets, sustained-release capsules or sustained-release tablets, wherein the sustained-release pellets are made of a pill core and an isolation layer, wherein the pill core comprises the following components in parts by weight: 5 parts of active ingredient ruxolitinib, microcrystalline cellulose pill core 100 40-60 parts, hydroxypropyl methylcellulose MK25000PFV 1-12 parts, talc 0.1-0.8 parts; the isolation layer includes the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1-3 parts, talc 1-3 parts.

[0019] In a preferred embodiment, the sustained-release preparation of ruxolitinib provided by the present invention is in the form of sustained-release pellets, sustained-release capsules or sustained-release tablets, wherein the sustained-release pellets are made of a pill core and an isolation layer, wherein the pill core comprises the following components in parts by weight: 5 parts of the active ingredient ruxolitinib, a microcrystalline cellulose pill core 100 50-55 parts, hydroxypropyl methylcellulose MK25000PFV 1.6-8 parts, talc 0.2-0.6 parts; the isolation layer includes the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1.2-1.8 parts, talc 1.2-1.8 parts.

[0020] In a more preferred embodiment, the sustained-release preparation of ruxolitinib provided by the present invention is in the form of sustained-release pellets, sustained-release capsules or sustained-release tablets, wherein the sustained-release pellets are made of a pill core and an isolation layer:

[0021] For example, the pill core includes the following components by weight: 5 parts of active ingredient ruxolitinib, microcrystalline cellulose pill core 100 53.6 parts, hydroxypropyl methylcellulose MK25000PFV 1.6 parts, talc 0.4 parts; the isolation layer includes the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1.6 parts, talc 1.6 parts.

[0022] For example, the pill core includes the following components by weight: 5 parts of active ingredient ruxolitinib, microcrystalline cellulose pill core 100 53.6 parts, hydroxypropyl methylcellulose MK25000PFV 4.8 parts, talc 0.4 parts; the isolation layer includes the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1.6 parts, talc 1.6 parts.

[0023] For example, the pill core includes the following components by weight: 5 parts of active ingredient ruxolitinib, microcrystalline cellulose pill core 100 53.6 parts, hydroxypropyl methylcellulose MK25000PFV 8 parts, talc 0.4 parts; the isolation layer includes the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1.6 parts, talc 1.6 parts.

[0024] In the present invention, the sustained-release pellets can be mixed with auxiliary materials and compressed into sustained-release tablets, wherein the auxiliary materials are diluents and lubricants, and the auxiliary materials include the following components in parts by weight: 70-100 parts of sorbitol and 1-3 parts of magnesium stearate.

[0025] In a preferred embodiment, the auxiliary materials include the following components in parts by weight: 87.4-93.8 parts of sorbitol and 2-2.5 parts of magnesium stearate.

[0026] In a more preferred embodiment, the auxiliary materials include the following components in parts by weight:

[0027] For example, the auxiliary materials include the following components in parts by weight: 93.8 parts of sorbitol and 2.4 parts of magnesium stearate.

[0028] For example, the auxiliary materials include the following components in parts by weight: 90.6 parts of sorbitol and 2.4 parts of magnesium stearate.

[0029] For example, the auxiliary materials include the following components in parts by weight: 87.4 parts of sorbitol and 2.4 parts of magnesium stearate.

[0030] The present invention also provides a method for preparing the sustained-release preparation of ruxolitinib, which comprises the following steps:

[0031] (1) Pretreatment: crush and sieve the active ingredients for later use;

[0032] (2) Preparation of drug-containing coating solution: The active ingredient ruxolitinib, a binder, and a glidant are stirred and uniformly dispersed in water to prepare a drug-containing coating solution;

[0033] (3) Preparation of isolation layer coating solution: stir and evenly disperse the binder and glidant in water to prepare isolation layer coating solution;

[0034] (4) placing the filler in a fluidized bed, coating the filler with the drug using the drug-containing coating solution obtained in step (2) as a binder solution, and drying the filler to prepare a drug-containing pellet core;

[0035] (5) placing the drug-containing pellet cores obtained in step (4) in a fluidized bed, coating them with the isolation layer coating solution obtained in step (3) as a binder solution, and drying them to prepare sustained-release pellets;

[0036] (6) The sustained-release pellets obtained in step (5) are filled into capsules to prepare sustained-release capsules; or the sustained-release pellets obtained in step (5) are mixed with auxiliary materials and compressed into sustained-release tablets.

[0037] In step (1), the active ingredient is crushed and passed through a 40-80 mesh sieve. The mesh number of the sieve may be, but is not limited to, 40 mesh, 50 mesh, 60 mesh, 70 mesh or 80 mesh. In a preferred embodiment, the mesh number of the sieve is 60 mesh.

[0038] In step (2), the mass content of the binder (e.g., hydroxypropyl methylcellulose MK25000PFV) in the drug-containing coating solution is 1%-5%, and can be but not limited to 1%, 2%, 3%, 4% or 5%. Preferably, the mass content of the binder (e.g., hydroxypropyl methylcellulose MK25000PFV) in the drug-containing coating solution is 3%.

[0039] In step (3), the mass content of the binder (e.g., hydroxypropyl methylcellulose MK25000PFV) in the isolation layer coating liquid is 0.5% to 3.5%, and can be but not limited to 0.5%, 1%, 1.5%, 2%, 2.5%, 3% or 3.5%. Preferably, the mass content of the binder (e.g., hydroxypropyl methylcellulose MK25000PFV) in the isolation layer coating liquid is 2%.

[0040] For the present invention, the drug coating is carried out in a fluidized bed, mainly to complete the conventional wet granulation and coating steps in a closed container at one time. The preparation method of the present invention can keep the drug in a suspended fluidized state under the action of the airflow from bottom to top, and the drug-containing coating liquid and the isolation layer coating liquid are sprayed into the fluidized chamber from the upper part or the lower part. The drug coating, pellet forming and drying of the material are all completed in the same fluidized bed equipment, which reduces a large number of operation links and saves production costs. Carrying out drug coating in a fluidized bed can also enable the preparation method to be carried out in a sealed environment, which can not only prevent the contamination of the drug by the outside world, but also reduce the chance of the operator contacting with irritating or toxic drugs and excipients.

[0041] In the process of drug coating in a fluidized bed, the present invention selects specific fillers, adhesives and glidants, as well as the ratio between the components, and parameter conditions in the granulation process. When other conditions are matched, not only can the stable release of the sustained-release preparation be guaranteed, but also the growth of impurities in the coating process is suppressed to the greatest extent, the content uniformity of the sustained-release preparation is effectively improved, and the total impurity content and the maximum single impurity content in the product are reduced; at the same time, the prepared sustained-release preparation has the advantages of uniform particle size, good fluidity and compression formability, slow dissolution, and no sticking, uniform content of drugs with lower content in the formula, saving production time, etc., which solves the problem of poor sustained-release effect and stability, and can solve the adverse effects of other preparation methods such as wet granulation.

[0042] Furthermore, the present invention uses a drug-containing aqueous solution and an isolation layer aqueous solution as coating solutions for drug coating and re-coating, respectively. The drying and coating temperatures must be controlled within an appropriate and reasonable range to suppress the growth of impurities during the drug coating process to the greatest extent, effectively improve the content uniformity of the sustained-release preparation, and reduce the total impurity content and the maximum single impurity content in the product. Too low drying and coating temperatures lead to micropill adhesion, making it difficult to obtain uniform micropills, and too high granulation and coating temperatures cause the growth of related substances, and the total impurity content and the maximum single impurity content are high.

[0043] In step (4), the parameters for drug coating are set as follows: air inlet temperature is 60°C, material temperature is 45-55°C, preferably 50°C, atomization pressure is 0.2-0.4MPa, liquid supply pump speed is 5-15rpm, fan air volume is 100-200m 3 / h; the drying temperature is 45-55°C, and the drying loss is controlled to be less than 2.0%. Preferably, the drying temperature is 50°C.

[0044] In step (5), the coating parameters are set as follows: air inlet temperature is 60°C, material temperature is 45-55°C, preferably 50°C, atomization pressure is 0.2-0.4MPa, liquid supply pump speed is 5-15rpm, fan air volume is 100-200m 3 / h; the drying temperature is 45-55°C, and the drying loss is controlled to be less than 2.0%. Preferably, the drying temperature is 50°C.

[0045] In step (6), the ruxolitinib sustained-release pellets obtained in step (5) are mixed with sorbitol, and the mixing speed is controlled to be 5-15 rpm and the mixing time is 5-10 min; preferably, the mixing speed is 10 rpm and the mixing time is 8 min; magnesium stearate is then added to the obtained mixture, and the mixing speed is controlled to be 5-15 rpm and the mixing time is 3-7 min, preferably, the mixing speed is 10 rpm and the mixing time is 5 min.

[0046] In a preferred embodiment, the method for preparing the sustained-release preparation of ruxolitinib comprises the following more detailed steps:

[0047] (1) Pretreatment: crush ruxolitinib through a 60-mesh sieve for later use;

[0048] (2) Preparation of drug-containing coating solution: Ruxolitinib, hydroxypropyl methylcellulose MK25000PFV, and talcum powder were stirred and uniformly dispersed in water to prepare a drug-containing coating solution with a mass content of 3% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0049] (3) Preparation of isolation layer coating liquid: Hydroxypropyl methylcellulose MK25000PFV and talcum powder are stirred and uniformly dispersed in water to prepare an isolation layer coating liquid with a mass content of 2% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0050] (4) Add microcrystalline cellulose pellets 100 is placed in a fluidized bed, and the drug-containing coating solution obtained in step (2) is used as a binder solution for drug coating. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare a pill core containing a drug;

[0051] (5) placing the pill cores obtained in step (4) in a fluidized bed, and coating them with the isolation layer coating solution obtained in step (3) as a binder solution. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare ruxolitinib sustained-release pellets;

[0052] (6) The ruxolitinib sustained-release pellets obtained in step (5) are loaded into No. 0-3 gelatin capsules to obtain ruxolitinib sustained-release capsules; or the ruxolitinib sustained-release pellets obtained in step (5) are mixed with sorbitol, the mixing speed is controlled to be 10 rpm, the mixing time is 8 min, magnesium stearate is added to the mixture, the mixing speed is controlled to be 10 rpm, the mixing time is 5 min, and tableting is performed to obtain ruxolitinib sustained-release tablets.

[0053] The method of the present invention is used to prepare the sustained-release preparation of ruxolitinib, without the need to use special equipment or involving special auxiliary materials, and solves the problems of poor stability, inability to release smoothly and complicated preparation methods of existing ruxolitinib phosphate tablets, and has the advantages of good sustained-release effect, good stability, low content of related substances and high clinical safety, and adopts a fluidized bed for drug coating, the whole preparation method is simple, has low requirements for production equipment, reduces production energy consumption, simplifies production steps, can ensure product quality and is suitable for large-scale industrial production. At the same time, hydroxypropyl methylcellulose 25000PFV is used as a coating component to well cover the bitter taste of the drug, which can greatly increase the compliance of patients, especially children, with medication.

[0054] Adopt the technical scheme of the present invention, the advantages are as follows:

[0055] The sustained-release preparation of ruxolitinib provided by the present invention can ensure the stable release of the sustained-release preparation by selecting specific fillers, adhesives and glidants, the ratio between the components, and the parameter conditions in the granulation process. Under the condition of matching other conditions, the growth of impurities in the coating process is suppressed to the greatest extent, the content uniformity of the sustained-release preparation is effectively improved, and the total impurity content and the maximum single impurity content in the product are reduced; at the same time, the prepared sustained-release preparation has the advantages of uniform particle size, good fluidity and compression formability, slow dissolution, no sticking, uniform drug content with a low content in the formula, saving production time, etc., solves the problem of poor sustained-release effect and stability, and can solve the adverse effects of other preparation methods such as wet granulation; on the other hand, it can reduce the number of medications and well mask the bitter taste of the drug, and is suitable for children.

[0056] The method provided by the present invention solves the problems of poor stability, inability to release smoothly and complex preparation method of the existing ruxolitinib phosphate tablets, and has the advantages of good sustained-release effect, good stability, low content of related substances and high clinical safety. A fluidized bed is used for drug coating, the entire preparation method is simple, the requirements for production equipment are low, production energy consumption is reduced, the production steps are simplified, product quality can be guaranteed and it is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0057] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0058] Example 1

[0059] A sustained-release preparation of ruxolitinib, the formula and dosage of each component are as follows:

[0060]

[0061] The method for preparing the sustained-release preparation of ruxolitinib comprises the following steps:

[0062] (1) Pretreatment: crush ruxolitinib through a 60-mesh sieve for later use;

[0063] (2) Preparation of drug-containing coating solution: Ruxolitinib, hydroxypropyl methylcellulose MK25000PFV, and talcum powder were stirred and uniformly dispersed in water to prepare a drug-containing coating solution with a mass content of 3% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0064] (3) Preparation of isolation layer coating liquid: Hydroxypropyl methylcellulose MK25000PFV and talcum powder are stirred and uniformly dispersed in water to prepare an isolation layer coating liquid with a mass content of 2% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0065] (4) Add microcrystalline cellulose pellets 100 is placed in a fluidized bed, and the drug-containing coating solution obtained in step (2) is used as a binder solution for drug coating. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare a pill core containing a drug;

[0066] (5) placing the pill cores obtained in step (4) in a fluidized bed, and coating them with the isolation layer coating solution obtained in step (3) as a binder solution. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare ruxolitinib sustained-release pellets;

[0067] (6) The ruxolitinib sustained-release pellets obtained in step (5) were mixed with sorbitol, the mixing speed was controlled to be 10 rpm, the mixing time was 8 min, magnesium stearate was added to the mixture, the mixing speed was controlled to be 10 rpm, the mixing time was 5 min, and tableting was performed to obtain ruxolitinib sustained-release tablets.

[0068] Example 2

[0069] A sustained-release preparation of ruxolitinib, the formula and dosage of each component are as follows:

[0070]

[0071] The method for preparing the sustained-release preparation of ruxolitinib comprises the following steps:

[0072] (1) Pretreatment: crush ruxolitinib through a 60-mesh sieve for later use;

[0073] (2) Preparation of drug-containing coating solution: Ruxolitinib, hydroxypropyl methylcellulose MK25000PFV, and talcum powder were stirred and uniformly dispersed in water to prepare a drug-containing coating solution with a mass content of 3% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0074] (3) Preparation of isolation layer coating liquid: Hydroxypropyl methylcellulose MK25000PFV and talcum powder are stirred and uniformly dispersed in water to prepare an isolation layer coating liquid with a mass content of 2% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0075] (4) Add microcrystalline cellulose pellets 100 is placed in a fluidized bed, and the drug-containing coating solution obtained in step (2) is used as a binder solution for drug coating. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare a pill core containing a drug;

[0076] (5) placing the pill cores obtained in step (4) in a fluidized bed, and coating them with the isolation layer coating solution obtained in step (3) as a binder solution. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after dry coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare ruxolitinib sustained-release pellets;

[0077] (6) The ruxolitinib sustained-release pellets obtained in step (5) were mixed with sorbitol, the mixing speed was controlled to be 10 rpm, the mixing time was 8 min, magnesium stearate was added to the mixture, the mixing speed was controlled to be 10 rpm, the mixing time was 5 min, and tableting was performed to obtain ruxolitinib sustained-release tablets.

[0078] Example 3

[0079] A sustained-release preparation of ruxolitinib, the formula and dosage of each component are as follows:

[0080]

[0081] The method for preparing the sustained-release preparation of ruxolitinib comprises the following steps:

[0082] (1) Pretreatment: crush ruxolitinib through a 60-mesh sieve for later use;

[0083] (2) Preparation of drug-containing coating solution: Ruxolitinib, hydroxypropyl methylcellulose MK25000PFV, and talcum powder were stirred and uniformly dispersed in water to prepare a drug-containing coating solution with a mass content of 3% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0084] (3) Preparation of isolation layer coating liquid: Hydroxypropyl methylcellulose MK25000PFV and talcum powder are stirred and uniformly dispersed in water to prepare an isolation layer coating liquid with a mass content of 2% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0085] (4) Add microcrystalline cellulose pellets 100 is placed in a fluidized bed, and the drug-containing coating solution obtained in step (2) is used as a binder solution for drug coating. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare a pill core containing a drug;

[0086] (5) placing the pill cores obtained in step (4) in a fluidized bed, and coating them with the isolation layer coating solution obtained in step (3) as a binder solution. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after dry coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare ruxolitinib sustained-release pellets;

[0087] (6) The ruxolitinib sustained-release pellets obtained in step (5) were mixed with sorbitol, the mixing speed was controlled to be 10 rpm, the mixing time was 8 min, magnesium stearate was added to the mixture, the mixing speed was controlled to be 10 rpm, the mixing time was 5 min, and tableting was performed to obtain ruxolitinib sustained-release tablets.

[0088] Example 4

[0089] A sustained-release preparation of ruxolitinib, the formula and dosage of each component are as follows:

[0090]

[0091] The method for preparing the sustained-release preparation of ruxolitinib comprises the following steps:

[0092] (1) Pretreatment: crush ruxolitinib through a 60-mesh sieve for later use;

[0093] (2) Preparation of drug-containing coating solution: Ruxolitinib, hydroxypropyl methylcellulose MK25000PFV, and talcum powder were stirred and uniformly dispersed in water to prepare a drug-containing coating solution with a mass content of 3% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0094] (3) Preparation of isolation layer coating liquid: Hydroxypropyl methylcellulose MK25000PFV and talcum powder are stirred and uniformly dispersed in water to prepare an isolation layer coating liquid with a mass content of 2% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0095] (4) Add microcrystalline cellulose pellets 100 is placed in a fluidized bed, and the drug-containing coating solution obtained in step (2) is used as a binder solution for drug coating. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare a pill core containing a drug;

[0096] (5) placing the pill cores obtained in step (4) in a fluidized bed, and coating them with the isolation layer coating solution obtained in step (3) as a binder solution. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare ruxolitinib sustained-release micropellets.

[0097] Example 5

[0098] A sustained-release preparation of ruxolitinib, the formula and dosage of each component are as follows:

[0099]

[0100]

[0101] The method for preparing the sustained-release preparation of ruxolitinib comprises the following steps:

[0102] (1) Pretreatment: crush ruxolitinib through a 60-mesh sieve for later use;

[0103] (2) Preparation of drug-containing coating solution: Ruxolitinib, hydroxypropyl methylcellulose MK25000PFV, and talcum powder were stirred and uniformly dispersed in water to prepare a drug-containing coating solution with a mass content of 3% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0104] (3) Preparation of isolation layer coating liquid: Hydroxypropyl methylcellulose MK25000PFV and talcum powder are stirred and uniformly dispersed in water to prepare an isolation layer coating liquid with a mass content of 2% of the binder hydroxypropyl methylcellulose MK25000PFV;

[0105] (4) Add microcrystalline cellulose pellets 100 is placed in a fluidized bed, and the drug-containing coating solution obtained in step (2) is used as a binder solution for drug coating. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare a pill core containing a drug;

[0106] (5) placing the pill cores obtained in step (4) in a fluidized bed, and coating them with the isolation layer coating solution obtained in step (3) as a binder solution. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; after coating, drying is performed at a drying temperature of 50°C, and the drying loss is controlled to be less than 2.0% to prepare ruxolitinib sustained-release pellets;

[0107] (6) The ruxolitinib sustained-release pellets obtained in step (5) are loaded into No. 0-No. 3 gelatin capsules to obtain ruxolitinib sustained-release capsules.

[0108] Comparative Example 1

[0109] A sustained-release preparation of ruxolitinib, the formula and dosage of each component are as follows:

[0110]

[0111] The preparation method of the sustained-release preparation of ruxolitinib is as described in Example 1.

[0112] Comparative Example 2

[0113] A sustained-release preparation of ruxolitinib, the formula and dosage of each component are as follows:

[0114]

[0115] The preparation method of the sustained-release preparation of ruxolitinib is as described in Example 1.

[0116] Comparative Example 3

[0117] A sustained-release preparation of ruxolitinib, the formula and dosage of each component are as follows:

[0118]

[0119] The preparation method of the sustained-release preparation of ruxolitinib is as described in Example 2.

[0120] Comparative Example 4

[0121] A sustained-release preparation of ruxolitinib, the formula and dosage of each component are as follows:

[0122]

[0123] The method for preparing the sustained-release preparation of ruxolitinib comprises the following steps:

[0124] (1) Pretreatment: crush ruxolitinib through a 60-mesh sieve for later use;

[0125] (2) Preparation of drug-containing coating solution: Ruxolitinib, hydroxypropyl methylcellulose K15M and talcum powder were stirred and uniformly dispersed in water to prepare a drug-containing coating solution with a mass content of 3% hydroxypropyl methylcellulose;

[0126] (3) Preparation of isolation layer coating solution: Hydroxypropyl methylcellulose K15M and talcum powder are stirred and uniformly dispersed in water to prepare an isolation layer coating solution having a mass content of 2% of the binder hydroxypropyl methylcellulose K15M;

[0127] (4) Add microcrystalline cellulose pellets 100 is placed in a fluidized bed, and the drug-containing coating solution obtained in step (2) is used as a binder solution for drug coating. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; drying after coating, the drying temperature is 50°C, and the drying loss is controlled to be less than 2.0%; making a pill core containing medicine;

[0128] (5) placing the pill cores obtained in step (4) in a fluidized bed, and coating them with the isolation layer coating solution obtained in step (3) as a binder solution. The parameters during coating are set as follows: inlet air temperature is 60° C., material temperature is 50° C., atomization pressure is 0.2-0.4 MPa, liquid supply pump speed is 5-15 rpm, and fan air volume is 100-200 m 3 / h; drying after coating, the drying temperature is 50°C, and the drying loss is controlled to be less than 2.0%, to obtain ruxolitinib sustained-release pellets;

[0129] (6) The ruxolitinib sustained-release pellets obtained in step (5) were mixed with sorbitol at a mixing speed of 10 rpm for 8 min, magnesium stearate was added to the mixture at a mixing speed of 10 rpm for 5 min, and tableting was performed to obtain ruxolitinib sustained-release tablets.

[0130] Comparative Example 5

[0131] Ruxolitinib phosphate tablets were prepared according to the components and methods of the examples in Chinese patent CN117298055A.

[0132] Comparative Example 6

[0133] Ruxolitinib phosphate tablets were prepared according to the components and method of Example 1 in Chinese patent CN118217255A.

[0134] Comparative Example 7

[0135] Ruxolitinib phosphate sustained-release tablets were prepared according to the components and method of Example 1 in Chinese patent CN113384545A.

[0136] Comparative Example 8

[0137] The drug-containing sustained-release pellets were prepared according to the components and methods in Example 1 of Chinese patent CN117815195A, and the drug-containing sustained-release pellets were mixed with 12 parts of microcrystalline cellulose, 2 parts of cross-linked polyvinylpyrrolidone, 0.5 parts of colloidal silicon dioxide and 0.5 parts of magnesium stearate, and finally tableted (tablet weight 115 mg, hardness 40-60N) to obtain ruxolitinib phosphate sustained-release tablets.

[0138] The effect analysis data are as follows:

[0139] (1) Bitterness evaluation

[0140] Take the preparations prepared in each embodiment and comparative example of the present invention, adopt a strict test method, and take a dosage of 5 mg of ruxolitinib. Select 40 healthy volunteers (half male and half female) who have passed the strict bitterness screening, hold the drug in the middle of the tongue, then put in 20 ml of water, time for 30 seconds, spit it out, and rinse the mouth several times until there is no odor in the mouth. After 30 minutes, test the bitterness of another drug. Volunteers score the bitterness according to the following table:

[0141] Table 1: Bitterness evaluation criteria

[0142]

[0143] The bitterness evaluation results of the preparations prepared in Examples 1 to 5 and Comparative Examples 1 to 8 are as follows:

[0144] Table 2 Scoring results

[0145] Serial number Bitterness Rating Example 1 9.50 Example 2 9.65 Example 3 9.70 Example 4 9.58 Example 5 9.55 Comparative Example 1 8.10 Comparative Example 2 8.60 Comparative Example 3 8.45 Comparative Example 4 8.28 Comparative Example 5 7.43 Comparative Example 6 6.50 Comparative Example 7 7.50 Comparative Example 8 8.15

[0146] As shown in Table 2, the present invention uses the adhesive hydroxypropyl methylcellulose MK25000PFV to coat the pill core. As shown in Examples 1, 2 and 3, as the amount thereof increases, the taste-masking effect is better. However, due to the high viscosity of the adhesive hydroxypropyl methylcellulose MK25000PFV, excessive use will hinder dissolution and bring risks to in vivo absorption. In Comparative Example 1, the amount of the adhesive hydroxypropyl methylcellulose MK25000PFV is low, and the taste-masking effect is reduced; in Comparative Example 2, the amount of the adhesive hydroxypropyl methylcellulose MK25000PFV is high, and the taste-masking effect is also reduced; therefore, the amount of the adhesive hydroxypropyl methylcellulose MK25000PFV needs to be controlled within a certain range to achieve a better taste-masking effect of the present invention. In Comparative Examples 3 and 4, the dosage of the binder hydroxypropyl methylcellulose MK25000PFV is too high or too low, which is not within the scope of protection of the present invention, and the taste-masking effect is poor; in Comparative Examples 5 and 7, wet granulation is adopted, and although the bitterness is acceptable, the compliance of patients and even children is reduced; Comparative Example 6 adopts electrospinning technology, and the taste-masking effect of electrospinning technology after dissolving the raw materials is not good; Comparative Example 8 adopts ethyl cellulose coating, which has a certain taste-masking effect, but the effect is general.

[0147] (2) Quality test indicators

[0148] The test results of sample content, related substances, etc. of the samples in the embodiments and comparative examples on day 0 are shown in Tables 3 and 4.

[0149] Table 3 Quality test results of Examples 1 to 5

[0150]

[0151] Table 4 Quality test results of comparative examples 1 to 8

[0152]

[0153] It can be seen from Tables 3 and 4 that the sustained-release preparations of ruxolitinib prepared by the formulation and method of the present application all meet the quality standards, have low moisture content, low impurity levels, and good content uniformity.

[0154] The test results of sample content, related substances, etc. of the samples in the embodiments and comparative examples after accelerated 6 months are shown in Tables 5 and 6.

[0155] Table 5: Results of the accelerated 6-month quality tests of Examples 1 to 5

[0156]

[0157] Table 6 Comparative Examples 1 to 8 Accelerated 6-month Quality Test Results

[0158]

[0159] As shown in Tables 5 and 6, the sustained-release preparations containing ruxolitinib prepared in Examples 1 to 5 of the present invention have low impurity levels, low moisture content, good content uniformity and good stability; the dosage of the binder hydroxypropyl methylcellulose MK25000PFV in Comparative Examples 1 to 3 is too high or too low, which is not within the scope of the present invention. After 6 months of acceleration, the content and related substances show a trend of increasing in detail, and the stability is poor; the binder in Comparative Example 4 is hydroxypropyl methylcellulose K15M, the model is not within the scope of protection of the present invention, its stability is poor, and the growth of related substances and moisture is more significant; Comparative Examples 5 and Comparative Example 7 are prepared according to the composition of Example 1 in Chinese Patents CN117298055A and CN113384545A. The granulation was carried out according to the preparation method of the invention. After 6 months of acceleration, the content and related substances showed a clear increasing trend, and the stability was poor, which illustrated the superiority of the preparation method and parameter conditions of the present invention; in Comparative Example 8, the ruxolitinib phosphate sustained-release tablets prepared according to the components and methods in Example 1 of Chinese Patent CN117815195A had a high impurity level and poor stability after 6 months of acceleration; in Comparative Example 6, the ruxolitinib phosphate tablets prepared by electrospinning technology according to the components and methods in Example 1 of Chinese Patent CN118217255A had a stability far worse than that of other embodiments and comparative examples after 6 months of acceleration, which illustrated the superiority of the formulation and preparation method of the present invention as a whole.

[0160] (3) Dissolution data test results:

[0161] The dissolution data of the ruxolitinib sustained-release preparations prepared in Examples 1 to 5 and Comparative Examples 1 to 8 in a pH 6.8 phosphate medium are shown in Tables 7 and 8.

[0162] Table 7 Cumulative dissolution data of ruxolitinib-related preparations prepared in Examples 1 to 5

[0163]

[0164]

[0165] Table 8 Cumulative dissolution data of ruxolitinib-related preparations prepared in Comparative Examples 1 to 8

[0166]

[0167] As shown in Table 7 and Table 8, the samples prepared according to the formula and method of the present invention in Examples 1 to 5 have good taste masking effect, uniformity, impurity level, stability and other indicators, and also have the effect of long-term synchronous release, which ensures the bioavailability of the product, can meet the effect of taking it once a day, and also improves the compliance of patients and children; the dosage of the adhesive hydroxypropyl methylcellulose MK25000PFV in Comparative Examples 1 to 3 is high or low, which is not within the scope of the present invention, and significantly affects the dissolution rate and stability; the adhesive in Comparative Example 4 is hydroxypropyl methylcellulose K15M, the model is not within the scope of the present invention, and its dissolution end point is short and the dissolution rate is fast; Comparative Examples 5 and Comparative Examples 6 are ordinary tablets, which show rapid dissolution, cannot meet the sustained release effect, and the moisture, impurity level and stability are far less than the present invention. Comparative Examples 7 and Comparative Examples 8 are sustained-release tablets, but they can be released completely in 12h, and the in vitro release time of the two is far less than the present invention. The long-acting release of the present invention can better alleviate the number of times patients take it.

[0168] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A sustained-release preparation of ruxolitinib, characterized in that: The dosage form of the sustained-release preparation is sustained-release micropellets, sustained-release capsules or sustained-release tablets, wherein the sustained-release micropellets are made of a pill core containing a drug and an isolation layer, the pill core containing a drug comprises an active ingredient ruxolitinib, a filler, a binder and a glidant, the isolation layer comprises a binder and a glidant, the sustained-release micropellets are filled into capsules to form sustained-release capsules; the sustained-release micropellets are then mixed with excipients and compressed into sustained-release tablets.

2. The sustained-release preparation according to claim 1, characterized in that The filler is microcrystalline cellulose pellets, preferably microcrystalline cellulose pellets 100; the binder is hydroxypropyl methylcellulose MK25000PFV; the glidant is one or more of silicon dioxide, talc or micro-powdered silica gel, preferably talc; the excipients are diluents and lubricants, wherein the diluent is one or more of microcrystalline cellulose, lactose, mannitol or sorbitol, preferably sorbitol; the lubricant is magnesium stearate and / or sodium stearyl fumarate, preferably magnesium stearate.

3. The sustained-release preparation according to claim 2, characterized in that The drug-containing pill core comprises the following components in parts by weight: 5 parts of the active ingredient ruxolitinib, microcrystalline cellulose pill core 100 40-60 parts, hydroxypropyl methylcellulose MK25000PFV 1-12 parts, talc 0.1-0.8 parts; the isolation layer comprises the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1-3 parts, talc 1-3 parts.

4. The sustained-release preparation according to claim 3, characterized in that The drug-containing pill core comprises the following components in parts by weight: 5 parts of the active ingredient ruxolitinib, microcrystalline cellulose pill core 100 50-55 parts, hydroxypropyl methylcellulose MK25000PFV 1.6-8 parts, talc 0.2-0.6 parts; the isolation layer comprises the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1.2-1.8 parts, talc 1.2-1.8 parts.

5. The sustained-release preparation according to claim 4, characterized in that The drug-containing pill core comprises the following components in parts by weight: 5 parts of the active ingredient ruxolitinib, microcrystalline cellulose pill core 100 53.6 parts, hydroxypropyl methylcellulose MK25000PFV 1.6 parts, talc 0.4 parts; the isolation layer comprises the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1.6 parts, talc 1.6 parts. The drug-containing pill core comprises the following components in parts by weight: 5 parts of the active ingredient ruxolitinib, microcrystalline cellulose pill core 100 53.6 parts, hydroxypropyl methylcellulose MK25000PFV 4.8 parts, talc 0.4 parts; the isolation layer comprises the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1.6 parts, talc 1.6 parts. The drug-containing pill core comprises the following components in parts by weight: 5 parts of the active ingredient ruxolitinib, microcrystalline cellulose pill core 100 53.6 parts, hydroxypropyl methylcellulose MK25000PFV 8 parts, talc 0.4 parts; the isolation layer comprises the following components in parts by weight: hydroxypropyl methylcellulose MK25000PFV 1.6 parts, talc 1.6 parts.

6. The sustained-release preparation according to claim 3, 4 or 5, characterized in that: The sustained-release pellets are then mixed with excipients and compressed into sustained-release tablets, wherein the excipients include the following components in parts by weight: 70-100 parts of sorbitol and 1-3 parts of magnesium stearate; preferably, the excipients include the following components in parts by weight: 87.4-93.8 parts of sorbitol and 2-2.5 parts of magnesium stearate; more preferably, the excipients include the following components in parts by weight: 93.8 parts of sorbitol and 2.4 parts of magnesium stearate; or, 90.6 parts of sorbitol and 2.4 parts of magnesium stearate; or, 87.4 parts of sorbitol and 2.4 parts of magnesium stearate.

7. The method for preparing the sustained-release preparation of ruxolitinib according to claim 1, characterized in that: It includes the following steps: (1) Pretreatment: crush and sieve the active ingredients for later use; (2) Preparation of drug-containing coating solution: The active ingredient ruxolitinib, a binder, and a glidant are stirred and uniformly dispersed in water to prepare a drug-containing coating solution; (3) Preparation of isolation layer coating solution: stir and evenly disperse the binder and glidant in water to prepare isolation layer coating solution; (4) placing the filler in a fluidized bed, coating the filler with the drug using the drug-containing coating solution obtained in step (2) as a binder solution, and drying the filler to prepare a drug-containing pellet core; (5) placing the drug-containing pellet cores obtained in step (4) in a fluidized bed, coating them with the isolation layer coating solution obtained in step (3) as a binder solution, and drying them to prepare sustained-release pellets; (6) The sustained-release pellets obtained in step (5) are filled into capsules to prepare sustained-release capsules; or the sustained-release pellets obtained in step (5) are mixed with auxiliary materials and compressed into sustained-release tablets.

8. The method for preparing the sustained-release preparation of ruxolitinib according to claim 7, characterized in that: The filler is microcrystalline cellulose pellets, preferably microcrystalline cellulose pellets 100; the binder is hydroxypropyl methylcellulose MK25000PFV; the glidant is one or more of silicon dioxide, talc or micro-powdered silica gel, preferably talc; the excipients are diluents and lubricants, wherein the diluent is one or more of microcrystalline cellulose, lactose, mannitol or sorbitol, preferably sorbitol; the lubricant is magnesium stearate and / or sodium stearyl fumarate, preferably magnesium stearate.

9. The method for preparing the sustained-release preparation of ruxolitinib according to claim 7, characterized in that: In step (1), the active ingredient is crushed through a 40-80 mesh sieve, preferably a 60 mesh sieve; in step (2), the mass content of the binder in the drug-containing coating solution is 1%-5%, preferably 3%; in step (3), the mass content of the binder in the isolation layer coating solution is 0.5%-3.5%, preferably 2%.

10. The method for preparing the sustained-release preparation of ruxolitinib according to claim 7, characterized in that: In step (4), the parameters for drug coating are set as follows: air inlet temperature is 60°C, material temperature is 45-55°C, preferably 50°C, atomization pressure is 0.2-0.4MPa, liquid supply pump speed is 5-15rpm, fan air volume is 100-200m 3 / h; the drying temperature is 45-55°C, and the drying loss is controlled to be less than 2.0%. Preferably, the drying temperature is 50°C; in step (5), the parameters during coating are set as follows: the inlet air temperature is 60°C, the material temperature is 45-55°C, preferably 50°C, the atomization pressure is 0.2-0.4MPa, the liquid supply pump speed is 5-15rpm, and the fan air volume is 100-200m 3 / h; the drying temperature is 45-55°C, and the drying loss is controlled to be less than 2.0%. Preferably, the drying temperature is 50°C.

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