Preparation method of rosaxostat capsule

Abstract

The invention relates to the technical field of medicine preparation, in particular to a preparation method of a rosaxostat capsule, which comprises the following steps: mixing two raw materials with different particle sizes with a filler, an adhesive and a disintegrating agent, granulating, and filling the granulated particles into a capsule shell; the two raw materials with different particle sizes are crushed in different crushing modes and can meet production requirements by using conventional crushing equipment, the particle sizes of the raw materials are easy to control, the requirement on crushing parameters of the equipment is low, and the controllability of particle size distribution of the raw materials is improved. The preparation method greatly reduces the requirements on the initial particle size of the raw materials and crushing equipment, is simple and feasible in process, is very convenient for large-scale production or transfer to a production site, and can ensure the stability of product quality to the greatest extent.

Description

Technical Field

[0001] The present invention relates to the technical field of medicine preparation, and more specifically, to a method for preparing roxadustat capsules. Background Art

[0002] Renal anemia is anemia caused by the progression of various chronic kidney diseases (CKD). It is often related to a variety of reasons, such as relative or absolute deficiency of erythropoietin secretion by the renal interstitium, reduced sensitivity of patients to it, shortened life span of red blood cells, changes in the microenvironment of the bone marrow hematopoietic system, and iron deficiency. Severe renal anemia will increase the mortality rate of CKD patients. There are about 119.5 million CKD patients in my country, of which about 400,000 are receiving dialysis (or peritoneal dialysis), and the number is increasing rapidly at a double-digit rate every year. Therefore, more and more patients need to treat renal anemia.

[0003] Roxadustat (RDXT), jointly developed by FibroGen, AstraZeneca and Astellas, is the world's first small molecule hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of chronic kidney disease (CKD). Roxadustat stabilizes HIF, inhibits its degradation, activates the transcription of related genes, produces corresponding physiological responses, moderately increases the concentration of erythropoietin, increases the sensitivity of erythropoietin (EPO) receptors, coordinates the production of red blood cells, reduces hepcidin levels, increases the content and activity of transferrin receptors, promotes iron absorption and utilization, and is well tolerated. This drug is the first global original research drug incubated in China and the first to be approved in China, and is used for dialysis-dependent chronic renal failure anemia.

[0004] The chemical name of rosuvastatin is [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid. The structural formula is as follows:

[0005]

[0006] In the production of APIs, particle size is an indispensable indicator. According to the dissolution requirements of different preparations, the particle size of the API should be controlled in different particle size segments to maximize the efficacy. The particle size distribution of the API may have a significant impact on the performance of the final product, such as solubility, bioavailability, content uniformity, and stability. In addition, the particle size distribution of the API will also affect the drug's fluidity, total mixing uniformity, compressibility and other manufacturability, which may then affect the safety, efficacy and quality of the drug.

[0007] In the consistency evaluation of generic drugs, particle size is a key quality attribute of some solid preparations. If the particle size is too large, the dissolution will be too slow, and if the particle size is too small, the dissolution will be too fast and cannot be consistent with the reference preparation. Rosuvastatin has poor water solubility, with a solubility in water of only 1.71 mg / L. It is a poorly soluble drug, and particle size has a significant impact on product quality.

[0008] Regarding the research report on the particle size control of roxadustat API, the original patent CN116199628B discloses a particle size control method for roxadustat API, whose particle size distribution D90 is about 21μm to 29μm; D50 is about 12μm to 17μm, and D10 is about 6μm to 10μm; however, the applicant has found through research that it is currently difficult to obtain roxadustat API that meets this requirement through conventional pulverization methods:

[0009] (1) It is difficult to crush the particle size of rosuvastatin API to less than 40 μm by mechanical crushing. The particle size is too large and the dissolution is slow.

[0010] (2) Air flow milling can easily crush the particle size of rosuvastatin API to less than 25 μm, which is too fine and dissolves too quickly.

[0011] This patent's requirement range for raw material particle size places extremely high demands on the stability of the crushing equipment and crushing process parameters. Stably crushing different batches of raw materials into this narrow range will be a severe challenge for the raw material crushing operation.

[0012] Patent CN113768886A discloses a rosuvastatin capsule preparation process, which solves the problem of poor solubility of rosuvastatin raw materials by dissolving the raw materials in an organic solvent to prepare a solid dispersion.

[0013] This preparation process does not require the raw materials to be crushed, but the large-scale use of organic solvents increases the production cost of the product and puts higher requirements on the production conditions for large-scale production. This problem will become more serious after the product is scaled up. In addition, there is also a risk of decreased solubility of the solid dispersion during the stability placement process.

[0014] Patent CN113956200A discloses a crystallization process for rosuvastatin raw materials, which controls the particle size of the final raw materials by controlling the crystallization process parameters during the raw material production process. This process requires strict control of the process parameters during the raw material production process, and places high demands on the raw material production process, especially when the batch size or production site of the raw material production changes, the reproducibility cannot be guaranteed.

[0015] The particle size of rosuvastatin raw materials has a significant effect on the dissolution of the raw materials. When the particle size is too large, the dissolution is slow, which may lead to incomplete dissolution; when the particle size is too small, the dissolution is too fast, which may lead to incomplete absorption in the body. Therefore, reasonable measures should be taken to avoid significant changes in the particle size of raw materials between different batches, and it is very challenging for existing pulverizing equipment to control the particle size of raw materials within a narrow range. Summary of the invention

[0016] In view of the above technical problems, the present invention provides a method for preparing rosuvastatin capsules; the preparation method combines two raw materials with different particle sizes in a certain proportion, and both raw materials with different particle sizes are easy to obtain and have good reproducibility. Even if the batch size changes, there is no need to adjust the process. The dissolution behavior of the final product can be controlled by controlling the reasonable ratio between the two raw materials with different particle sizes.

[0017] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0018] A method for preparing rosuvastatin capsules comprises the steps of mixing two raw materials with different particle sizes with a filler, a binder and a disintegrant, granulating, drying and granulating the raw materials, mixing the granulated particles with a lubricant and filling the granules into a capsule shell; the two raw materials with different particle sizes are pulverized by different pulverization methods.

[0019] Preferably, the raw material of the first particle size among the two different particle sizes is crushed by means of a jet mill, and the raw material of the second particle size is crushed by means of a mechanical mill.

[0020] Preferably, the following preparation steps are adopted:

[0021] S1. Preparation of the first particle size raw material: crushing the raw material by a jet mill;

[0022] S2, preparation of raw materials of the second particle size: crushing the raw materials by a mechanical crusher;

[0023] S3, granulation: the two raw materials prepared in S1 and S2 are placed in a wet granulator and mixed evenly with a filler, a binder, and a disintegrant, and granulated by high-speed stirring and shearing;

[0024] S4, the wet granules obtained in step S3 are sieved and wet-granulated, placed in a fluidized bed granulator and coated for drying, and the dry granules are granulated by a granulator;

[0025] S5, placing the dry particles obtained in step S4 in a hopper mixer, adding a lubricant and mixing evenly;

[0026] S6. Capsule filling: Fill the prepared granules into capsule shells.

[0027] Preferably, the particle size distribution of the first particle size raw material is D90 less than 20 μm, and the particle size distribution of the second particle size raw material is D90 between 40 μm and 60 μm.

[0028] Preferably, the first particle size raw material accounts for 5% to 7% of the total weight, and the second particle size raw material accounts for 6 to 10% of the total weight.

[0029] Preferably, in the S3, the filler accounts for 20-80% of the total weight, the binder accounts for 2-10% of the total weight, the disintegrant accounts for 2-20% of the total weight, and the lubricant accounts for 0.2-2% of the total weight.

[0030] Preferably, the capsule shell adopts any one of No. 1, No. 2, No. 3, and No. 4 capsules.

[0031] Preferably, the binder is one or two of hydroxypropyl cellulose, povidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and methyl cellulose; the filler is one or two of lactose, microcrystalline cellulose, pregelatinized starch, dextrin, and starch; and the disintegrant is one or a mixture of two of cross-linked povidone, dry starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

[0032] Preferably, the lubricant is any one of magnesium stearate, sodium stearyl fumarate, and polyethylene glycol.

[0033] Preferably, the granulation is performed by wet granulation.

[0034] The beneficial effects of the present invention are as follows:

[0035] The present invention uses two raw materials of different particle sizes to form a combination, which reduces the requirements for pulverizing equipment and parameter control, making the raw material particle size control simpler. The raw material of the first particle size is processed by an air flow pulverizer, and the raw material particle size can reach the required range without strictly controlling the parameters of the air flow pulverizer; the raw material of the second particle size is processed by a mechanical pulverizer, and the raw material particles can reach the required range by only controlling the mesh number of the mechanical pulverizer, without controlling other parameters. The raw materials of the two particle sizes can meet the requirements by only combining them in a suitable ratio.

[0036] The present invention has no special requirements for the initial particle size of the raw materials, so no special requirements are required for the raw material synthesis and crystallization process, no special requirements are required for the crushing equipment and crushing process parameters, and no organic solvent is required, which greatly reduces the production cost and the requirements for production equipment and process parameters. The granulation, total mixing and capsule filling of the materials of the present invention are simple to operate, and the obtained particles have uniform particle size and good fluidity. DETAILED DESCRIPTION

[0037] In order to more clearly understand the above-mentioned purpose, features and advantages of the present invention, the present invention is further described in detail below in conjunction with specific embodiments. It should be noted that the embodiments of the present application and the features in the embodiments can be combined with each other without conflict.

[0038] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from the description. Therefore, the protection scope of the present invention is not limited to the specific embodiments disclosed below.

[0039] Embodiment 1

[0040] Prescribing Information:

[0041]

[0042] Preparation method:

[0043] 1. The rosuvastatin raw material was subjected to air flow grinding, and the particle size distribution was controlled to be less than 10 μm at D90.

[0044] 2. The rosuvastatin raw material was mechanically crushed through 120 mesh, and the particle size distribution was controlled so that D90 was between 40 and 50 μm.

[0045] 3. According to the prescription, weigh the raw materials of two particle sizes, lactose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and dissolve povidone K30 in an appropriate amount of purified water to make a binder solution. Add the weighed materials to the wet granulator. Turn on the stirring paddle to mix the raw materials and auxiliary materials evenly. Spray all the binders into the granulator, and dry the obtained granules at a temperature of 60°C until LOD ≤ 3.0% before discharging.

[0046] 4. The dried material is granulated using a 0.5mm round hole sieve.

[0047] 5. Calculate the amount of magnesium stearate to be added based on the amount of granules after dry granulation, weigh the magnesium stearate, add the magnesium stearate into the mixing barrel, set the mixing speed to 10 rpm, and the mixing time to 5 minutes.

[0048] 6. Capsule filling: Fill the prepared granules into appropriate capsule shells.

[0049] Embodiment 2

[0050] Prescribing Information:

[0051]

[0052] The preparation method is the same as in Example 1

[0053] Dissolution Assay:

[0054] The dissolution curve of the sample was determined according to the self-designed dissolution curve determination method, the medium was pH 6.5 buffer, and compared with the reference preparation sample of this product (manufacturer: FibroGen (China) Pharmaceutical Technology Development Co., Ltd., specification: 50 mg). The dissolution curve results are shown in Table 1.

[0055] Table 1. Comparison of dissolution results of Examples 1 and 2 with the reference preparation in pH 6.5 medium

[0056]

[0057] The dissolution of the self-made product is consistent with that of the reference preparation. The preparation process is simple, feasible and easy to realize industrial large-scale production, and the quality is the same as that of the reference preparation.

[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may also have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing roxadustat capsules, characterized in that: The two raw materials with different particle sizes are mixed with a filler, a binder and a disintegrant, and then granulated, dried and sized. The granules after size adjustment are mixed with a lubricant and then filled into a capsule shell; the two raw materials with different particle sizes are pulverized by different pulverization methods.

2. The method for preparing roxadustat capsules according to claim 1, characterized in that: The first particle size raw material of the two different particle sizes is crushed by a jet mill, and the second particle size raw material is crushed by a mechanical mill.

3. The method for preparing roxadustat capsules according to claim 1, characterized in that: The following preparation steps were used: S1. Preparation of the first particle size raw material: crushing the raw material by a jet mill; S2, preparation of raw materials of the second particle size: crushing the raw materials by a mechanical crusher; S3, granulation: the two raw materials prepared in S1 and S2 are placed in a wet granulator and mixed evenly with a filler, a binder, and a disintegrant, and granulated by high-speed stirring and shearing; S4, the wet granules obtained in step S3 are sieved and wet-granulated, placed in a fluidized bed granulator for drying, and the dry granules are sieved by a granulator; S5, placing the dry particles obtained in step S4 in a hopper mixer, adding a lubricant and mixing evenly; S6. Capsule filling: Fill the prepared granules into capsule shells.

4. A method for preparing roxadustat capsules according to any one of claims 1 to 3, characterized in that: The first particle size raw material has a particle size distribution of D90 less than 20 μm, and the second particle size raw material has a particle size distribution of D90 between 40 μm and 60 μm.

5. A method for preparing roxadustat capsules according to any one of claims 1 to 3, characterized in that: The first particle size raw material accounts for 5% to 7% of the total weight, and the second particle size raw material accounts for 6% to 10% of the total weight.

6. The method for preparing roxadustat capsules according to claim 3, characterized in that: In the S3, the filler accounts for 20-80% of the total weight, the binder accounts for 2-10% of the total weight, the disintegrant accounts for 2-20% of the total weight, and the lubricant accounts for 0.2-2% of the total weight.

7. A method for preparing roxadustat capsules according to any one of claims 1 to 3, characterized in that: The capsule shell adopts any one of No. 1, No. 2, No. 3 and No. 4 capsules.

8. A method for preparing roxadustat capsules according to any one of claims 1 to 3, characterized in that: The binder is one or two of hydroxypropyl cellulose, povidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and methyl cellulose; the filler is one or two of lactose, microcrystalline cellulose, pregelatinized starch, dextrin, and starch; and the disintegrant is one or a mixture of two of cross-linked povidone, dry starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

9. The method for preparing roxadustat capsules according to claim 3, characterized in that: The lubricant is any one of magnesium stearate, sodium stearyl fumarate and polyethylene glycol.

10. A method for preparing roxadustat capsules according to any one of claims 1 to 3, characterized in that: The granulation is performed by wet granulation.

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