Preparation method of riociguat tablet

Abstract

The invention discloses a preparation method of riociguat tablets, and belongs to the technical field of pharmaceutical preparations, the preparation method comprises the following steps: step 1, micronizing a main drug until the particle size D90 is less than or equal to 10 [mu] m for later use, step 2, adding a surfactant accounting for 0.1-1% (W / W) of a tablet core in the form of dry powder, the preparation method comprises the following steps: 1, uniformly mixing a micronized main drug, a filler, a disintegrating agent and other materials, preparing a binder into a solution, spraying the solution into a fluidized bed, carrying out fluidization granulation, and drying, 2, screening and finishing the particles obtained in step 2, 4, adding a lubricant into the dry particles obtained in step 3, uniformly mixing to obtain total mixed particles, and 5, granulating the total mixed particles to obtain a finished product. The preparation method comprises the following steps of 1, preparing the total mixed particles, 2, preparing the total mixed particles, 3, preparing the total mixed particles, 4, preparing the total mixed particles, 5, placing the total mixed particles prepared in the step 4 in a tablet press for tabletting to prepare the riociguat tablet core, 6, coating the riociguat tablet core prepared in the step 5 to prepare the riociguat tablet, and solving the technical problems that in the prior art, the cost is high, the process reproducibility is poor, and crystal transformation and degradation risks exist. The preparation method is mainly applied to preparation of riociguat tablets.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing riociguat tablets. Background Art

[0002] Riociguat (Adempas), the first new class of soluble guanylate cyclase (SGC) agonists developed and marketed by Bayer, is the world's first drug approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and the only drug currently with dual indications for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

[0003] The chemical name of Riociguat is 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidine(methyl)carbamate, and its molecular formula is C 20 H 19 FN8O2, molecular weight is 422.42, CAS number is 625115-55-1, and the structural formula is as follows:

[0004]

[0005] Riociguat is a low-solubility crystalline drug. Riociguat itself has extremely poor solubility, which is the decisive factor limiting the in vitro dissolution and in vivo absorption of the preparation;

[0006] Patent Publication No. (CN117064860A) discloses a preparation method of riociguat tablets, and the specific steps of the preparation method are as follows: S1: the main drug is micronized into different particle sizes and mixed evenly for use; S2. The micronized main drug, filler, disintegrant and binder are mixed evenly, and wet granulation is performed with a solubilizer to obtain a soft material; S3: the soft material is passed through a sieve to obtain wet granules, and placed in a boiling drying granulator for drying, and passed through a sieve to obtain dry granules; S4: a lubricant is added to the dry granules and mixed evenly to obtain a total mixed granule; S5: the total mixed granule is placed in a tablet press for tableting to obtain a tablet core; S6: the tablet core is coated with a coating powder to obtain a film-coated tablet to obtain a riociguat tablet;

[0007] The above preparation method requires the API to be finely powdered into different particle sizes and then mixed, which is cumbersome to operate and not conducive to commercial production and cost control;

[0008] Patent Publication No. (CN106913554A) discloses a method for preparing a preparation for treating pulmonary arterial hypertension, and the preparation process comprises: pretreatment of raw materials, micronization of riociguat to a desired particle size, dispersing riociguat in an aqueous solution of a binder + a solubilizer, adding granulation excipients to a fluidized bed, spraying the drug solution into the fluidized bed, and granulating in a fluidized bed in one step;

[0009] The above preparation method disperses the micronized API into the adhesive, which may cause the raw material sedimentation and poor process reproducibility. In addition, the state of the raw material in the adhesive solution is unstable, with the risk of crystal transformation and degradation. Summary of the invention

[0010] Purpose of the invention: The purpose of the present invention is to provide a method for preparing riociguat tablets to solve the technical problems of high cost, poor process reproducibility, and risk of crystal transformation and degradation in the prior art.

[0011] The above technical objectives of the present invention are achieved through the following technical solutions: A method for preparing riociguat tablets, comprising the following steps:

[0012] (1) Micronize the main drug to a particle size of D90 ≤ 10 μm for later use;

[0013] (2) The percentage of surfactant in the tablet core is in the range of 0.1% to 1% (W / W), and the surfactant is added in the form of dry powder, mixed evenly with the micronized main drug, filler, disintegrant and other materials, and the binder is prepared into a solution, sprayed into a fluidized bed, fluidized granulated, and dried;

[0014] (3) sieving the granules obtained in step (2) to obtain dry granules;

[0015] (4) adding a lubricant to the dry granules obtained in step (3) and mixing them uniformly to obtain total mixed granules;

[0016] (5) placing the total mixed granules obtained in step (4) on a tablet press to obtain riociguat tablet cores;

[0017] (6) coating the riociguat tablet core obtained in step (5) to obtain riociguat tablets.

[0018] Furthermore: in the step (1), the particle size D90 of the main drug is ≤5 μm.

[0019] Furthermore, in step (2), the main drug is riociguat, the fillers are lactose and microcrystalline cellulose, the disintegrant is cross-linked polyvinylpyrrolidone, the binder is hypromellose, and the surfactant is sodium lauryl sulfate.

[0020] Furthermore, in the step (2), the main drug and the auxiliary drug account for 0.5% to 3.0% of the total weight of the drug as the main drug riociguat, 30% to 50% of the filler lactose, 30% to 50% of the filler microcrystalline cellulose, 5% to 10% of the disintegrant cross-linked polyvinylpyrrolidone, 2% to 5% of the binder hypromellose, and 0.1% to 1% of the surfactant sodium lauryl sulfate.

[0021] Furthermore, in step (4), the lubricant is magnesium stearate, which accounts for 0.25% to 1% of the total weight of the drug.

[0022] Compared with the prior art, the present invention has the following advantages: the API and sodium lauryl sulfate powder are added to the material, and the fluidized granulation process is adopted to avoid the risk of API crystallization and degradation in the suspended state. The dissolution curve of the product is highly similar to that of the reference preparation. It is also conducive to commercial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is a dissolution curve diagram of the dissolution medium of the present invention. DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the accompanying drawings in the embodiments of the present invention;

[0025] It should be noted that, in the absence of conflict, the features in the embodiments of the present application may be combined with each other.

[0026] The following description is used to fully understand the present invention, however, the present invention can also be implemented in other ways different from the description;

[0027] Therefore, the protection scope of the present invention is not limited by the specific embodiments disclosed below.

[0028] Embodiment 1:

[0029] 1. Prescription

[0030]

[0031]

[0032] 2. Preparation

[0033] (1) Micronize the main drug, riociguat, to a particle size D90 ≤ 10 μm for later use;

[0034] (2) Mix micronized riociguat, microcrystalline cellulose, lactose monohydrate, crospovidone and sodium lauryl sulfate evenly, place in a fluidized bed, prepare a solution with hypromellose, spray into the fluidized bed, perform fluidized granulation, and dry;

[0035] (3) granulating the granules prepared in step (2) by a granulator to obtain dry granules;

[0036] (4) adding magnesium stearate to the dry granules obtained in step (3) and mixing them uniformly to obtain total mixed granules;

[0037] (5) placing the total mixed granules prepared in step (4) on a tablet press to prepare riociguat tablet cores; (6) coating the riociguat tablet cores prepared in step (5) to prepare riociguat tablets.

[0038] Embodiment 2:

[0039] 1. Prescription

[0040]

[0041]

[0042] 2. Preparation

[0043] (2) Micronizing the main drug riociguat to a particle size of D90 ≤ 10 μm for later use;

[0044] (2) Mix micronized riociguat, microcrystalline cellulose, lactose monohydrate, crospovidone and sodium lauryl sulfate evenly, place in a fluidized bed, prepare a solution with hypromellose, spray into the fluidized bed, perform fluidized granulation, and dry;

[0045] (3) granulating the granules prepared in step (2) by a granulator to obtain dry granules;

[0046] (4) adding magnesium stearate to the dry granules obtained in step (3) and mixing them uniformly to obtain total mixed granules;

[0047] (5) placing the total mixed granules obtained in step (4) on a tablet press to obtain riociguat tablet cores;

[0048] (6) coating the riociguat tablet core obtained in step (5) to obtain riociguat tablets.

[0049] Embodiment 3:

[0050] 1. Prescription

[0051]

[0052]

[0053] 2. Preparation

[0054] (1) Micronize the main drug, riociguat, to a particle size D90 ≤ 10 μm for later use;

[0055] (2) Mix micronized riociguat, microcrystalline cellulose, lactose monohydrate, crospovidone and sodium lauryl sulfate evenly, place in a fluidized bed, prepare a solution with hypromellose, spray into the fluidized bed, perform fluidized granulation, and dry;

[0056] (3) granulating the granules prepared in step (2) by a granulator to obtain dry granules;

[0057] (4) adding magnesium stearate to the dried granules obtained in step (3) and mixing them uniformly to obtain a total mixed granule;

[0058] (5) placing the total mixed granules obtained in step (4) on a tablet press to obtain riociguat tablet cores;

[0059] (6) Coating the riociguat tablet core obtained in step (5) to obtain riociguat tablets.

[0060] 1. Prescription

[0061]

[0062] 2. Preparation

[0063] (1) Micronize the main drug, riociguat, to a particle size D90 ≤ 10 μm for later use;

[0064] (2) placing the micronized riociguat, microcrystalline cellulose, lactose monohydrate, crospovidone, hypromellose and sodium lauryl sulfate (dry powder) in step (1) in a wet granulation pot and mixing them evenly, spraying purified water into the granulation pot, wet granulating, and drying;

[0065] (3) granulating the wet soft material through a granulator, and then fluidizing and drying it to control the moisture content to ≤5.0%; (4) sieving the granules obtained in step (3) to obtain dry granules;

[0066] (5) adding magnesium stearate to the dried granules obtained in step (4) and mixing them uniformly to obtain a total mixed granule;

[0067] (6) placing the total mixed granules obtained in step (5) on a tablet press to obtain riociguat tablet cores;

[0068] (7) Coating the riociguat tablet core obtained in step (6) to obtain riociguat tablets.

[0069] 1. Prescription

[0070]

[0071] 2. Preparation

[0072] (1) Micronize the main drug, riociguat, to a particle size D90 ≤ 10 μm for later use;

[0073] (2) The micronized riociguat, microcrystalline cellulose, lactose monohydrate, and crospovidone prepared in step (1) are placed in a wet granulation pot and mixed evenly, and the prescribed amount of hydroxypropyl methylcellulose and sodium lauryl sulfate are placed in pure water, stirred to dissolve, and then sprayed into the granulation pot for wet granulation and fluidized drying;

[0074] (3) The wet soft material is granulated by a granulator, and then fluidized drying is performed to control the moisture content to ≤5.0%;

[0075] (4) screening the granules obtained in step (3) to obtain dry granules;

[0076] (5) adding magnesium stearate to the dried granules obtained in step (4) and mixing them uniformly to obtain a total mixed granule;

[0077] (6) placing the total mixed granules obtained in step (5) on a tablet press to obtain riociguat tablet cores;

[0078] (7) Coating the riociguat tablet core obtained in step (6) to obtain riociguat tablets.

[0079] 1. Prescription

[0080]

[0081] 2. Preparation

[0082] (1) Micronize the main drug, riociguat, to a particle size D90 ≤ 10 μm for later use;

[0083] (2) placing the micronized riociguat, microcrystalline cellulose, lactose monohydrate, crospovidone, hypromellose and sodium lauryl sulfate (dry powder) prepared in step (1) in a wet granulation pot and mixing them evenly;

[0084] (3) adding magnesium stearate to the material obtained in step (2) and mixing them uniformly to obtain a total mixed powder;

[0085] (4) placing the total mixed powder obtained in step (3) on a tablet press to tablet;

[0086] (5) Coating the riociguat tablet core obtained in step (4) to obtain riociguat tablets.

[0087] 1. Prescription

[0088]

[0089] 2. Preparation

[0090] (1) Micronize the main drug, riociguat, to a particle size D90 ≤ 10 μm for later use;

[0091] (2) Mix the micronized riociguat, microcrystalline cellulose, lactose monohydrate and crospovidone prepared in step (1), add the prescribed amount of hydroxypropyl methylcellulose and sodium lauryl sulfate in purified water, stir to dissolve, spray into a fluidized bed, perform fluidized granulation, and dry;

[0092] (3) sieve the granules obtained in step (2) to obtain dry granules;

[0093] (4) adding magnesium stearate to the dried granules obtained in step (3) and mixing them uniformly to obtain a total mixed granule;

[0094] (5) placing the total mixed granules obtained in step (4) on a tablet press to obtain riociguat tablet cores;

[0095] (6) Coating the riociguat tablet core obtained in step (5) to obtain riociguat tablets.

[0096] 1. Prescription

[0097]

[0098]

[0099] 2. Preparation

[0100] (1) Micronize the main drug, riociguat, to a particle size D90 ≤ 10 μm for later use;

[0101] (2) Mix microcrystalline cellulose, lactose monohydrate, and crospovidone evenly, add the prescribed amount of hydroxypropyl methylcellulose and sodium lauryl sulfate in purified water, stir to dissolve, add micronized riociguat, shear at high speed to form a suspension, spray into a fluidized bed, perform fluidized granulation, continue stirring during the granulation process, and dry after the granulation is completed;

[0102] (3) sieve the granules obtained in step (2) to obtain dry granules;

[0103] (4) adding magnesium stearate to the dried granules obtained in step (3) and mixing them uniformly to obtain a total mixed granule;

[0104] (5) placing the total mixed granules obtained in step (4) on a tablet press to obtain riociguat tablet cores;

[0105] (6) coating the riociguat tablet core obtained in step (5) to obtain riociguat tablets.

[0106] Test Example 1:

[0107] Dissolution test: Take samples of Examples 1-3 and Comparative Examples 1-5, and place the sample tablets of the Examples and Comparative Examples in a pH 6.8 phosphate buffer dissolution medium for dissolution testing according to the 2020 edition of the Chinese Pharmacopoeia, Part II, 0931 Dissolution Assay Method 2, and compare them with the reference preparation (trade name Adempas, batch number BXJVEF2, national medicine standard number HJ20170360, manufacturer Bayer AG). Sampling and detection are performed at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, and 90 min. The dissolution curve is as follows: Figure 1 As shown, the dissolution curve data is obtained according to the dissolution curve:

[0108]

[0109] Note: F2 calculation formula:

[0110] The calculated values ​​of the similarity factor f2 of Example 1, Example 2, and Example 3 with the reference preparation are 61, 84, and 51>50, respectively, which are similar to the dissolution curves of the reference preparation, but Comparative Examples 1 to 5 are all <50, which are not similar to the reference preparation.

[0111] Test Example 2:

[0112] Granulation stability test: The stability of the material during the granulation process was investigated. Except for Comparative Example 5, the raw materials of other embodiments and comparative examples were added as dry powders, so there was no need to investigate the stability of the granulation process. Comparative Example 5 was a suspension, and its stability was investigated.

[0113]

[0114] In Comparative Example 5, the API is added to a solvent to prepare a suspension, and the fluidized granulation process has the risk of API degradation, which poses a risk to the quality of the finished preparation.

[0115] The above description is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several improvements without departing from the principle of the present invention. These improvements should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing riociguat tablets, characterized in that: The following steps are involved: (1) Micronize the main drug to a particle size of D90 ≤ 10 μm for later use; (2) The percentage of surfactant in the tablet core is in the range of 0.1% to 1% (W / W), and the surfactant is added in the form of dry powder, mixed evenly with the micronized main drug, filler, disintegrant and other materials, and the binder is prepared into a solution, sprayed into a fluidized bed, fluidized granulated, and dried; (3) sieving the granules obtained in step (2) to obtain dry granules; (4) adding a lubricant to the dry granules obtained in step (3) and mixing them uniformly to obtain total mixed granules; (5) placing the total mixed granules obtained in step (4) on a tablet press to obtain riociguat tablet cores; (6) coating the riociguat tablet core obtained in step (5) to obtain riociguat tablets.

2. The method for preparing riociguat tablets according to claim 1, characterized in that: In the step (1), the particle size D90 of the main drug is ≤10 μm.

3. The method for preparing riociguat tablets according to claim 2, characterized in that: In the step (2), the main drug is riociguat, the fillers are lactose and microcrystalline cellulose, the disintegrant is cross-linked polyvinylpyrrolidone, the binder is hypromellose, and the surfactant is sodium lauryl sulfate.

4. The method for preparing riociguat tablets according to claim 1, characterized in that: In step (2), the main drug and the auxiliary drugs account for 0.5% to 3.0% of the total weight of the drug as the main drug riociguat, 30% to 50% of the filler lactose, 30% to 50% of the filler microcrystalline cellulose, 5% to 10% of the disintegrant cross-linked polyvinylpyrrolidone, 2% to 5% of the binder hypromellose, and 0.1% to 1% of the surfactant sodium lauryl sulfate.

5. The method for preparing riociguat tablets according to claim 1, characterized in that: In the step (4), the lubricant is magnesium stearate, which accounts for 0.25% to 1% of the total weight of the drug.

Images