Riociguat oral preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a riociguat oral preparation and a preparation method thereof. The invention aims to solve the problems of low solubility and difficulty in giving consideration to both quick-release administration and long-acting administration. The invention provides a riociguat oral preparation which comprises a drug-containing tablet core, a drug-containing quick-release part and a drug-containing slow-release part, wherein the drug-containing quick-release part and the drug-containing slow-release part are coated on the outer layer; the drug-containing quick-release part comprises the following components: riociguat, a first filler, a first disintegrating agent, a first adhesive, a first cosolvent and a first lubricant; the drug-containing sustained-release part comprises the following components: riociguat, a second filler, a second adhesive, a second cosolvent, a second lubricant, a sustained-release material and a flow aid; the drug-containing tablet core comprises a drug-containing inner core and a coating outer layer, and the drug-containing inner core comprises the following components: riociguat, a third filler, a second disintegrating agent, a third adhesive, a third cosolvent and a third lubricant. The invention also provides a method for preparing the Ociguat oral preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and more specifically, to a riociguat oral preparation and a preparation method thereof. Background Art

[0002] Pulmonary hypertension has always been regarded as the "cancer" of cardiovascular diseases, because its clinical symptoms lack specificity and are easily misdiagnosed. The disease occurs at a relatively low age, with 75% of patients concentrated between 20 and 40 years old, and the natural prognosis is poor, with a 5-year survival rate of only 21%.

[0003] Riociguat (Adempas) is the first drug in its class approved by the U.S. FDA to treat pulmonary hypertension and the first drug of any class to be shown to be effective in patients with chronic thromboembolic pulmonary hypertension (CTEPH); at the same time, in the European Union, Riociguat (Adempas) is the first and only drug approved for the treatment of CTEPH.

[0004] Riociguat has poor water solubility. In order to improve the dissolution performance, the prior art has proposed a variety of solutions for riociguat oral preparations, such as:

[0005] (1) Patent CN104434845B - A solid pharmaceutical preparation containing riociguat. The patent found in the research that the solid dispersion technology can be used to evenly disperse the drug in the carrier and form a colloidal solution with the carrier, which can effectively improve the dissolution rate and solubility of the drug and increase the absorption of the drug. In the present invention, polyethylene glycol is used as a water-soluble drug carrier, mixed with the active substance for melting, stirring, solidification, and crushing, and then mixed with other excipients, tableted, and coated to improve the solubility of riociguat in the preparation.

[0006] (2) Patent CN105596311A - A riociguat oral preparation and its preparation method. The solid pharmaceutical preparation provided adopts solid dispersion technology. By mixing and grinding the main drug, filler, and 50% disintegrant, the solubility of the main drug is improved, the dissolution effect is enhanced, and the preparation dissolution rate is fast, the content uniformity is high, and the bioavailability is high.

[0007] (3) Patent CN117064860A-CN117064860A provides a method for preparing riociguat tablets: the main drug is micronized into different particle sizes and mixed evenly for use; the micronized main drug, filler, disintegrant and binder are mixed evenly and wet granulated with a solubilizer to obtain a soft material; the soft material is passed through a sieve to obtain wet granules, which are placed in a boiling drying granulator for drying, and passed through a sieve to obtain dry granules; a lubricant is added to the dry granules and mixed evenly to obtain a total mixed granule; the total mixed granule is placed in a tablet press for tableting to obtain a tablet core; the tablet core is coated with a coating powder to obtain a film-coated tablet to obtain a riociguat tablet.

[0008] (4) Patent CN117771199A - A riociguat sustained-release tablet and its preparation method, discloses that under the joint action of active substances, fillers, sustained-release skeletons, adhesives, disintegrants, etc., the drug release rate can be controlled by controlling the hydration rate and the rate of expansion or diffusion of the tablets, thereby achieving the sustained release of riociguat and reducing the number of times patients take the drug.

[0009] However, the prior art oral preparations of riociguat have many deficiencies, including:

[0010] 1. The solid dispersion technology has complicated production process and relatively complex preparation, which easily leads to high labor, time and production costs;

[0011] 2. Ordinary mixing, grinding and dispersing technology will cause serious adsorption, thus affecting the content, and adding more excipients to the prescription will affect the stability of the preparation;

[0012] 3. The fluidized bed spray process is complex and unstable;

[0013] 4. Ordinary sustained-release preparations have the risk of poor absorption of the poorly soluble drug riociguat, resulting in insufficient efficacy.

[0014] In view of this, it is necessary to improve the existing riociguat oral preparations and their preparation processes. Summary of the invention

[0015] The present invention aims to overcome at least one defect of the above-mentioned prior art and provide a riociguat oral preparation and a preparation method thereof, which are used to solve the problems of low solubility of riociguat and difficulty in taking into account both rapid-release and long-acting administration.

[0016] The first aspect of the present invention is to provide a riociguat oral preparation, comprising a drug-containing shell and a drug-containing tablet core, wherein the drug-containing tablet core is embedded in the surface of the drug-containing shell or the drug-containing shell completely wraps the drug-containing tablet core;

[0017] The drug-containing shell includes a drug-containing immediate-release portion and a drug-containing sustained-release portion, wherein the components of the drug-containing immediate-release portion include: a first riociguat active ingredient, a first filler, a first disintegrant, a first binder, a first solubilizing agent, and a first lubricant; the components of the drug-containing sustained-release portion include: a second riociguat active ingredient, a second filler, a second binder, a second solubilizing agent, a second lubricant, a sustained-release material, and a glidant;

[0018] The drug-containing tablet core comprises a drug-containing inner core and a coating outer layer, wherein the coating outer layer covers the drug-containing inner core; the components of the drug-containing inner core comprise: a third riociguat active ingredient, a third filler, a second disintegrant, a third binder, a third cosolvent and a third lubricant.

[0019] The present invention provides a drug-containing sustained-release part and a drug-containing rapid-release part to be coated on the surface of the drug-containing tablet core, and the surface layer of the drug-containing tablet core is also provided with a coating outer layer to delay the drug release rate of the drug-containing inner core, thereby obtaining a riociguat oral preparation with three different drug release properties. The drug-containing rapid-release part can quickly dissolve part of riociguat, so as to quickly take effect on the patient, and the drug-containing sustained-release part can slowly release part of riociguat, so as to achieve the purpose of lasting effect. At the same time, by extending the dissolution time, the dissolution rate of riociguat can be improved, and the bioavailability can be improved; in addition, the drug-containing rapid-release part and the drug-containing sustained-release part of the external drug-containing tablet core are dissolved to a certain extent before they begin to be exposed and dissolved, so that a certain amount of riociguat compensation is provided in the rapid-release stage dominated by the drug-containing rapid-release part and the sustained-release stage dominated by the drug-containing sustained-release part, which can avoid the rapid administration of the rapid-release part on the one hand, so as to improve the safety of the patient's medication, and on the other hand, it can prevent the insufficient administration of the drug-containing sustained-release part, so as to ensure long-term effect. Therefore, compared with common sustained-release preparations, the riociguat oral preparation of the present invention has higher solubility and better absorption; compared with common immediate-release preparations, it can provide a stable sustained-release effect without sudden release, thereby achieving the purpose of long-term sustained-release and efficient treatment of pulmonary hypertension.

[0020] The second aspect of the present invention is to provide a method for preparing the riociguat oral preparation, comprising the following steps:

[0021] The first riociguat active ingredient, the first filler, the first disintegrant, the first binder, the first solubilizer and the first lubricant are wet granulated to obtain drug-containing immediate-release granules; the second riociguat active ingredient, the second filler, the second binder, the second solubilizer, the second lubricant, the sustained-release material and the glidant are wet granulated to obtain drug-containing sustained-release granules; the third riociguat active ingredient, the third filler, the second disintegrant, the third binder, the third solubilizer and the third lubricant are wet granulated and then tableted to obtain the drug-containing inner core, and the drug-containing inner core is coated with the coating outer layer to obtain the drug-containing tablet core;

[0022] The drug-containing immediate-release granules, the drug-containing sustained-release granules and the drug-containing tablet core are mixed, and the drug-containing immediate-release granules and the drug-containing sustained-release granules are coated on the surface of the drug-containing tablet core for tableting, and then subjected to a coating process to obtain the riociguat oral preparation, wherein the drug-containing immediate-release granules form the drug-containing immediate-release part, and the drug-containing sustained-release granules form the drug-containing sustained-release part.

[0023] Furthermore, the first filler includes a first main filler and a first co-powder filler, and in the process of preparing the drug-containing immediate-release granules, the first riociguat active ingredient and the first co-powder filler are mixed in advance and then co-crushed to obtain a first riociguat co-crushed mixture, which is then wet granulated; and / or,

[0024] The second filler includes a second main filler and a second co-powder filler. In the process of preparing the drug-containing sustained-release granules, the second riociguat active ingredient and the second co-powder filler are mixed in advance and then co-crushed to obtain a second riociguat co-crushed mixture, which is then wet granulated; and / or,

[0025] The third filler includes a third main filler and a third co-powder filler. In the process of preparing the drug-containing inner core, the third riociguat active ingredient and the third co-powder filler are mixed in advance and then co-crushed to obtain a third riociguat co-crushed mixture, which is then wet granulated.

[0026] The present invention can increase the specific surface area of ​​the riociguat active ingredient in the preparation, and can avoid the undesirable phenomenon that adsorption occurs when conventional pulverization is too fine, resulting in a decrease in the content of the active ingredient, thereby improving the solubility and release rate of riociguat, so as to obtain a higher bioavailability, and reduce the amount of riociguat in the preparation while ensuring the efficacy.

[0027] Preferably, the ratio of the first riociguat active ingredient to the first co-powder filler is 1:5 to 1:30 by weight; and / or,

[0028] The ratio of the second riociguat active ingredient to the second co-powder filler is 1:5 to 1:30; and / or,

[0029] The ratio of the third riociguat active ingredient to the third co-powder filler is 1:5 to 1:30; and / or,

[0030] The co-crushing time of the first riociguat active ingredient and the first co-powder filler is 30s to 60s; and / or,

[0031] The co-crushing time of the second riociguat active ingredient and the second co-powder filler is 30s to 60s; and / or,

[0032] The co-crushing time of the third riociguat active ingredient and the third co-powder filler is 30s to 60s.

[0033] Compared with the prior art, the present invention has the following beneficial effects: the present invention enables the oral riociguat preparation to have multiple drug release properties by combining a drug-containing immediate-release portion, a drug-containing sustained-release portion and a drug-containing tablet core. Compared with ordinary sustained-release preparations, the present preparation has higher solubility and better absorption; compared with ordinary immediate-release preparations, the present preparation provides a stable sustained-release effect without sudden release, thereby achieving the purpose of long-term sustained-release and high-efficiency treatment of pulmonary hypertension; secondly, by co-crushing, the specific surface area is increased to improve the solubility while accelerating the release rate of the active substance, and the preparation product is stable, the process steps are simple, the parameter control is stable, and the repeatability is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The cross-sectional structure of the riociguat oral preparation of the present invention is shown in FIG. Figure 1 .

[0035] Figure 2 The cross-sectional structure of the riociguat oral preparation of the present invention is shown in FIG. Figure 2 .

[0036] Figure 3 The cross-sectional structure of the riociguat oral preparation of the present invention is shown in FIG. Figure 3 .

[0037] Figure 4 The cross-sectional structure of the riociguat oral preparation of the present invention is shown in FIG. Figure 4 .

[0038] Figure 5 The cross-sectional structure of the riociguat oral preparation of the present invention is shown in FIG. Figure 5 .

[0039] Reference numerals: drug-containing outer shell 1, drug-containing immediate-release portion 11, drug-containing sustained-release portion 12, drug-containing tablet core 2. DETAILED DESCRIPTION

[0040] like Figure 1-5 As shown, the first aspect of the present invention is to provide a riociguat oral preparation, comprising a drug-containing shell 1 and a drug-containing tablet core 2. In some embodiments, reference Figure 1 , 4 , the drug-containing shell 1 is completely coated on the surface of the drug-containing tablet core 2, and in some other embodiments, reference Figure 2 , 3 5. The drug-containing tablet core 2 can also be embedded in the surface of the drug-containing shell 1. In this case, part of the drug-containing tablet core 2 is exposed on the surface of the drug-containing shell. Figure 2 , 3 5. Specifically, one of the surfaces of the drug-containing tablet core 2 may be exposed on the surface of the drug-containing shell 1. This method helps the drug-containing tablet core 2 to contact with the external solvent and can ensure that the drug-containing tablet core 2 and the drug-containing shell 1 are stably combined.

[0041] Specifically, the drug-containing shell 1 includes a drug-containing immediate-release portion 11 and a drug-containing sustained-release portion 12, wherein the components of the drug-containing immediate-release portion 11 include: a first riociguat active ingredient, a first filler, a first disintegrant, a first binder, a first solubilizing agent, and a first lubricant; the components of the drug-containing sustained-release portion 12 include: a second riociguat active ingredient, a second filler, a second binder, a second solubilizing agent, a second lubricant, a sustained-release material, and a glidant;

[0042] The drug-containing tablet core 2 includes a drug-containing inner core and a coating outer layer, and the coating outer layer covers the drug-containing inner core; the components of the drug-containing inner core include: a third riociguat active ingredient, a third filler, a second disintegrant, a third binder, a third cosolvent and a third lubricant.

[0043] In addition, in order to facilitate the control of the riociguat component content in the three drug-containing layers, in specific implementation, the first riociguat active ingredient, the second riociguat active ingredient, and the third riociguat active ingredient all use riociguat raw materials with consistent specifications.

[0044] Since there are many ways to mix the drug-containing parts, there can be many positions between the drug-containing core 2 and the drug-containing immediate-release part 11 and the drug-containing sustained-release part 12. In some embodiments, for example Figure 1 , 3 5, the drug-containing tablet core 2 is completely embedded in the drug-containing sustained-release portion 12. In other embodiments, such as Figure 2 , 4 As shown, a portion of the drug-containing core 2 is embedded in the drug-containing sustained-release portion 12, and another portion of the drug-containing core 2 is embedded in the drug-containing immediate-release portion 11. It should be noted that tests have shown that Figure 1-5 These formulation structures shown do not affect the dissolution testing of the present invention.

[0045] The present invention combines a drug-containing sustained-release portion 12, a drug-containing rapid-release portion 11 and a drug-containing tablet core 2, and the surface of the drug-containing tablet core 2 is also provided with a coating outer layer to delay the drug release rate of the drug-containing inner core, thereby obtaining a riociguat oral preparation with three different drug release properties. The drug-containing rapid-release portion 11 can quickly dissolve part of the riociguat, so that it can quickly take effect on the patient, and the drug-containing sustained-release portion 12 can slowly release part of the riociguat, so as to achieve the purpose of lasting effect. At the same time, by extending the dissolution time, the dissolution rate of riociguat can be increased, and the bioavailability can be increased; in addition, the drug-containing tablet core 2 can provide a certain amount of riociguat compensation in both the rapid-release stage dominated by the drug-containing rapid-release portion 11 and the sustained-release stage dominated by the drug-containing sustained-release portion 12. On the one hand, it can avoid the rapid-release portion from being administered too quickly to improve the safety of the patient's medication, and on the other hand, it can prevent the drug-containing sustained-release portion 12 from being insufficiently administered to ensure long-term effect. Therefore, compared with common sustained-release preparations, the riociguat oral preparation of the present invention has higher solubility and better absorption; compared with common immediate-release preparations, it can provide a stable sustained-release effect without sudden release, thereby achieving the purpose of long-term sustained-release and efficient treatment of pulmonary hypertension.

[0046] In some embodiments, the content of the first riociguat active ingredient in the drug-containing immediate-release portion 11 is 0.2-2% by weight; and / or, the content of the second riociguat active ingredient in the drug-containing sustained-release portion 12 is 0.2-2%; and / or, the content of the third riociguat active ingredient in the drug-containing inner core is 0.2-2%. Tests show that by controlling the content of the riociguat active ingredient in the three drug-containing layers to 0.2-2%, the dissolution of riociguat at 2h, 12h, 24h, etc. can meet the quality control requirements, which can ensure that the dissolution amount required for rapid onset of effect is met, and can ensure long-term onset of effect within 24h, thereby reducing the number of times patients take the drug and improving medication compliance.

[0047] In some embodiments, the weight ratio of the first riociguat active ingredient, the second riociguat active ingredient, and the third riociguat active ingredient is (0.8-1.2): (2-6): (0.8-1.2). In specific implementation, it can be set to 1:2:1, 1:3:1, 1:4:1, 1:5:1, 1:6:1, etc. Tests show that when the ratio of the second riociguat active ingredient is increased, the API content in the drug-containing sustained-release portion is too high, causing a significant decrease in dissolution, resulting in the dissolution within 24 hours failing to meet the qualified standard requirements, affecting the efficacy of the preparation; when the ratio of the second riociguat active ingredient is decreased, the API content in the immediate-release portion is too high. Although the short-term dissolution rate increases, it will lead to incomplete dissolution and reduce the bioavailability of the product.

[0048] Furthermore, the coating outer layer includes an isolation coating layer and an enteric coating layer, and the isolation coating layer and the enteric coating layer are coated on the surface of the drug-containing inner core from the inside to the outside.

[0049] In a preferred embodiment, in order to make the riociguat release rate of the drug-containing core meet the requirements, the ratio of the weight of the isolation coating layer to the weight of the drug-containing core is (2-5):100, and the ratio of the weight of the enteric coating to the weight of the drug-containing core is (8-12):100.

[0050] In a specific implementation, in order to provide protection and provide a certain drug release control function, the riociguat oral preparation also includes a film coating layer, and the film coating layer is coated on the surface of the drug-containing shell 1.

[0051] In some embodiments, the first filler, the second filler, or the third filler is selected from any one or more of lactose, microcrystalline cellulose, mannitol, starch, or pregelatinized starch.

[0052] In some embodiments, the first disintegrant or the second disintegrant is selected from any one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and partially pregelatinized starch.

[0053] In some embodiments, the first binder, the second binder, or the third binder is selected from any one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, or hydroxypropyl cellulose.

[0054] In some embodiments, the first cosolvent, the second cosolvent, or the third cosolvent is selected from any one or more of Tween-80, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene-polyoxypropylene copolymers, glycerol, sodium stearate, calcium stearate, sodium lauryl sulfate, and fatty acid glycerides.

[0055] In some embodiments, the first lubricant, the second lubricant, or the third lubricant is selected from any one of talc, hydrogenated vegetable oil, sodium stearyl fumarate, or magnesium stearate.

[0056] In some embodiments, the sustained-release material is selected from any one or more of hydroxypropylmethylcellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate, carbomer or polyethylene oxide.

[0057] In some embodiments, the glidant is selected from colloidal silicon dioxide or talc.

[0058] In some embodiments, the drug-containing immediate-release portion 11 includes the following components, measured by weight: 0.2-2 parts of the first riociguat active ingredient; 3-10 parts of the first disintegrant; 75-95 parts of the first filler; 1-10 parts of the first binder; 0.2-3 parts of the first lubricant; and 0.02-0.2 parts of the first co-solvent.

[0059] In some embodiments, the drug-containing sustained-release portion 12 comprises the following components in parts by weight:

[0060] The second riociguat active ingredient is 0.2-2 parts; the second filler is 55-75 parts; the second adhesive is 1-10 parts; the second lubricant is 0.2-3 parts; the second solubilizer is 0.02-0.5 parts; the sustained-release material is 20-40 parts; and the glidant is 0.2-3 parts.

[0061] In some embodiments, the tablet core 2 includes the following components, measured by weight: 0.2-2 parts of the third riociguat active ingredient; 3-10 parts of the second disintegrant; 75-95 parts of the third filler; 1-10 parts of the third binder; 0.2-3 parts of the third lubricant; and 0.02-0.5 parts of the third co-solvent.

[0062] The second aspect of the present invention is to provide a method for preparing the above-mentioned riociguat oral preparation, comprising the following steps:

[0063] S1. The first riociguat active ingredient, the first filler, the first disintegrant, the first binder, the first solubilizer and the first lubricant are wet granulated to obtain drug-containing immediate-release granules; the second riociguat active ingredient, the second filler, the second binder, the second solubilizer, the second lubricant, the sustained-release material and the glidant are wet granulated to obtain drug-containing sustained-release granules; the third riociguat active ingredient, the third filler, the second disintegrant, the third binder, the third solubilizer and the third lubricant are wet granulated and then tableted to obtain a drug-containing inner core, and the drug-containing inner core is coated with a coating outer layer to obtain a drug-containing tablet core 2;

[0064] S2. The drug-containing immediate-release granules, the drug-containing sustained-release granules and the drug-containing tablet core 2 are mixed and compressed into tablets, and then subjected to a coating process to obtain a riociguat oral preparation, wherein the drug-containing immediate-release granules form a drug-containing immediate-release portion 11, and the drug-containing sustained-release granules form a drug-containing sustained-release portion 12.

[0065] Furthermore, the first filler includes a first main filler and a first co-powder filler. In step S1, in the process of preparing the drug-containing immediate-release granules, the first riociguat active ingredient and the first co-powder filler are mixed in advance and then co-crushed to obtain a first riociguat co-crushed mixture, which is then wet granulated; and / or,

[0066] The second filler includes a second main filler and a second co-powder filler. In the process of preparing the drug-containing sustained-release granules, the second riociguat active ingredient and the second co-powder filler are mixed in advance and then co-crushed to obtain a second riociguat co-crushed mixture, which is then wet granulated; and / or,

[0067] The third filler includes a third main filler and a third co-powder filler. In the process of preparing the drug-containing inner core, the third riociguat active ingredient and the third co-powder filler are mixed in advance and then co-crushed to obtain a third riociguat co-crushed mixture, which is then wet granulated.

[0068] Tests have shown that the method of co-grinding riociguat and some fillers in advance can increase the specific surface area of ​​the riociguat active ingredient in the preparation and avoid the undesirable phenomenon of adsorption resulting in a decrease in the active ingredient content when conventional grinding is too fine, thereby improving the solubility and release rate of riociguat to obtain higher bioavailability and reducing the amount of riociguat in the preparation while ensuring the efficacy.

[0069] In some embodiments, the ratio of the first riociguat active ingredient to the first co-powder filler is 1:5 to 1:30 by weight; and / or, the ratio of the second riociguat active ingredient to the second co-powder filler is 1:5 to 1:30; and / or, the ratio of the third riociguat active ingredient to the third co-powder filler is 1:5 to 1:30.

[0070] The test shows that when the weight ratio of riociguat to the co-powder filler is greater than 1:5, for example, 1:3, the riociguat is not completely crushed, causing the solubility of riociguat to decrease, and the dissolution at the three test time points of 2h, 12h and 24h cannot meet the established standard requirements; and when the weight ratio of riociguat to the co-powder filler is less than 1:30, for example, 1:35, due to the small amount of the total amount of riociguat, the degree of crushing of riociguat is insufficient at the same time, resulting in a decrease in dissolution and failure to meet the qualified standard requirements.

[0071] In some embodiments, the co-crushing time of the first riociguat active ingredient and the first co-powder filler is 30s to 60s; and / or, the co-crushing time of the second riociguat active ingredient and the second co-powder filler is 30s to 60s; and / or, the co-crushing time of the third riociguat active ingredient and the third co-powder filler is 30s to 60s.

[0072] The test showed that when the co-crushing time was less than 30 seconds, the crushing effect of Riociguat deteriorated, resulting in a decrease in dissolution and failure to meet the qualified standard requirements.

[0073] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0074] The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, methods and instruments used are conventional materials, reagents, methods and instruments in the art unless otherwise specified, and can be obtained through commercial channels by those skilled in the art.

[0075] Example 1

[0076] This embodiment provides a riociguat oral preparation, the formula of which is shown in Table 1:

[0077] Table 1. Formula ingredients of Riociguat oral preparation of Example 1:

[0078]

[0079] The preparation process of this embodiment is as follows:

[0080] S100. Weigh the API of the drug-containing immediate release part and the co-powder filler, pre-mix them, and then co-crush and sieve them to obtain the co-crushed API of the drug-containing immediate release part, prepare the co-solvent into a granulation liquid, weigh the corresponding main filler, disintegrant, binder, pre-mix them with the co-crushed API of the drug-containing immediate release part, add the granulation liquid to perform wet granulation and drying, weigh the corresponding lubricant and mix it with the granulated particles to obtain drug-containing immediate release granules;

[0081] Weighing the API of the drug-containing sustained-release part and the co-powder filler, premixing them, and then co-crushing and sieving them to obtain the co-crushed API of the drug-containing sustained-release part, preparing the co-solvent into a granulation liquid, weighing the corresponding main filler, adhesive, and sustained-release material, premixing them with the co-crushed API of the drug-containing sustained-release part, adding the granulation liquid to perform wet granulation and drying, weighing the corresponding glidant and lubricant, and mixing them with the granulated particles to obtain drug-containing sustained-release particles;

[0082] Weighing the API containing the tablet core and the co-powder filler, premixing them, and then co-crushing and sieving them to obtain the co-crushed API containing the tablet core, preparing a granulation liquid with a co-solvent, weighing the corresponding filler, binder, and disintegrant, premixing them with the co-crushed API containing the tablet core, adding the granulation liquid to perform wet granulation and drying, weighing the corresponding lubricant and mixing it with the granules after granulation to obtain tablet core-containing particles; taking the prescribed amount of the obtained tablet core-containing particles, respectively performing tablet compression, isolation coating, and enteric coating to obtain tablet cores;

[0083] S200. A tablet press is used to press the core-coated tablets. The drug-containing sustained-release granules in S100 are placed in the die of the tablet press. The drug-containing tablet core obtained in S100 is placed on the drug-containing sustained-release granules, pre-pressed, and then the prescribed amount of drug-containing immediate-release granules is placed in the die and pressed into tablets to obtain core-coated tablets; the core-coated tablets are then coated to obtain core-coated tablets, which are the riociguat oral preparations of the present invention.

[0084] In step S100, the API containing the immediate-release portion, the API containing the sustained-release portion, the API containing the tablet core portion and the corresponding co-powder filler are co-crushed for 45 seconds.

[0085] In a preferred embodiment, since the weight ratio of the API of the drug-containing immediate-release part, the API of the drug-containing sustained-release part, and the API of the drug-containing tablet core part to the corresponding co-powder filler is the same 1:15, and microcrystalline cellulose is used as the co-powder filler, in order to simplify the co-crushing process, the API required for the three drug-containing parts and the total required co-powder filler are premixed together and then co-crushed and sieved, so as to first obtain the total co-crushed API, and then according to the amount of API required by the drug-containing immediate-release part, the drug-containing sustained-release part, and the drug-containing tablet core part, the total co-crushed API is distributed to obtain the co-crushed API of the drug-containing immediate-release part, the co-crushed API of the drug-containing sustained-release part, and the co-crushed API of the drug-containing tablet core part. Afterwards, referring to the above-mentioned S100 step, the drug-containing immediate-release granules, the drug-containing sustained-release granules, and the drug-containing tablet core are prepared respectively. It can be understood that the use of this API co-crushing method can also ensure the consistency of the API processing degree in different drug-containing parts, which can also help reduce the individual deviation of the batch-produced riociguat oral preparations, improve production controllability, and thus improve product quality.

[0086] Example 2

[0087] This embodiment provides a riociguat oral preparation, and the formula of this embodiment is shown in Table 2:

[0088] Table 2. Formula ingredients of Riociguat oral preparation of Example 2

[0089]

[0090]

[0091] Preparation process: The preparation process of this embodiment is the same as that of embodiment 1.

[0092] Example 3

[0093] This embodiment provides an oral riociguat preparation. Compared with Example 1, the components of Example 3 are exactly the same, and the weight proportion of API in each drug-containing part is also the same. The difference mainly lies in the preparation process. Specifically, in the process of co-grinding the API and the filler, the weight ratio of the API in each drug-containing part to the co-grinding filler is adjusted to 1:5. The specific formula is shown in Table 3:

[0094] Table 3. Formula ingredients of Riociguat oral preparation of Example 3

[0095]

[0096] Example 4

[0097] This embodiment provides an oral riociguat preparation. Compared with Example 1, the components of Example 3 are exactly the same, and the weight proportion of API in each drug-containing part is also the same. The difference mainly lies in the preparation process. Specifically, in the process of co-grinding the API and the filler, the weight ratio of the API in each drug-containing part to the co-grinding filler is adjusted to 1:30. The specific formula is shown in Table 4:

[0098] Table 4. Composition of the oral preparation of Riociguat in Example 4

[0099]

[0100]

[0101] Preparation process: The preparation process of this embodiment is the same as that of embodiment 1.

[0102] Example 5

[0103] This embodiment provides an oral preparation of riociguat. Compared with Example 1, the components and proportions of Example 5 are exactly the same, and the only difference is the preparation process. Specifically, in the process of co-grinding the API and the filler, the co-grinding time of the API of each drug-containing layer and the co-powder filler in Example 5 is set to 30s.

[0104] Example 6

[0105] This embodiment provides an oral preparation of riociguat. Compared with Example 1, the components and proportions of Example 6 are exactly the same, and the only difference is the preparation process. Specifically, in the process of co-grinding the API and the filler, the co-grinding time of the API and the co-powder filler in each drug-containing layer of Example 6 is set to 60s.

[0106] Example 7

[0107] This example provides an oral preparation of riociguat. Compared with Example 1, the only difference of Example 7 is that the sustained-release material in the drug-containing sustained-release portion is replaced with a combination of "hydroxypropyl methylcellulose K200M+hydroxypropyl methylcellulose K100LV". The specific formula is shown in Table 5:

[0108] Table 5. Composition of the oral preparation of Riociguat in Example 7

[0109]

[0110]

[0111] Preparation process: The preparation process of this embodiment is the same as that of embodiment 1.

[0112] Example 8

[0113] This embodiment provides an oral preparation of riociguat. Compared with Embodiment 1, the difference of Embodiment 8 is that the weight proportion of the sustained-release material in the drug-containing sustained-release portion is reduced to 20%. The specific formula is shown in Table 6:

[0114] Table 6. Composition of the oral preparation of Riociguat in Example 8

[0115]

[0116]

[0117] Preparation process: The preparation process of this embodiment is the same as that of embodiment 1.

[0118] Example 9

[0119] This embodiment provides an oral preparation of riociguat. Compared with Embodiment 1, the difference of Embodiment 9 is that the weight proportion of the sustained-release material in the drug-containing sustained-release portion is increased to 40%. The specific formula is shown in Table 7:

[0120] Table 7. Formula ingredients of Riociguat oral preparation of Example 9

[0121]

[0122] Preparation process: The preparation process of this embodiment is the same as that of embodiment 1.

[0123] Example 10

[0124] This embodiment provides an oral preparation of riociguat. Compared with Embodiment 1, the difference of Embodiment 10 is that the weight proportion of the disintegrant in the drug-containing immediate-release portion and the drug-containing tablet core is reduced to 3%. The specific formula is shown in Table 8:

[0125] Table 8. Composition of the oral preparation of Riociguat in Example 10

[0126]

[0127] Preparation process: The preparation process of this embodiment is the same as that of embodiment 1.

[0128] Embodiment 11

[0129] This example provides an oral preparation of riociguat. Compared with Example 1, the difference of Example 11 is that the weight proportion of the disintegrant in the drug-containing immediate-release portion and the drug-containing tablet core is increased to 10%. The specific formula is shown in Table 9:

[0130] Table 9. Composition of the oral preparation of Riociguat in Example 11

[0131]

[0132]

[0133] Preparation process: The preparation process of this embodiment is the same as that of embodiment 1.

[0134] Example 12

[0135] This embodiment provides an oral preparation of riociguat. Compared with Embodiment 1, the difference of Embodiment 12 is that the disintegrant in the drug-containing immediate-release portion and the drug-containing tablet core is replaced with sodium carboxymethyl starch.

[0136] Preparation process: The preparation process of this embodiment is the same as that of embodiment 1.

[0137] Comparative Example 1

[0138] This comparative example provides a riociguat oral preparation, the formulation ingredients are exactly the same as those in Example 1, and the total API prescription amount is also the same, except that the API content of the drug-containing immediate release portion is reduced to 0.13%. The specific formulation is shown in Table 10:

[0139] Table 10. Comparative Example 1 Riociguat oral preparation formulation composition table

[0140]

[0141]

[0142] Comparative Example 2

[0143] This comparative example provides a riociguat oral preparation, the formulation ingredients are exactly the same as those in Example 1, except that the API content of the drug-containing immediate-release portion and the drug-containing sustained-release portion is increased. The specific formulation is shown in Table 11:

[0144] Table 11. Comparative Example 2 Riociguat oral preparation formulation composition table

[0145]

[0146] Comparative Example 3

[0147] This comparative example provides a riociguat oral preparation. Compared with Example 1, the components of Comparative Example 3 are exactly the same, and the API ratio of each drug-containing part is also consistent. The difference mainly lies in the preparation process. Specifically, in the process of co-grinding the API and the filler, the weight ratio of the API to the co-powdered filler is adjusted to 1:3. The specific formula is shown in Table 12:

[0148] Table 12. Comparative Example 3 Riociguat oral preparation formulation composition table

[0149]

[0150] Comparative Example 4

[0151] This comparative example provides a riociguat oral preparation. Compared with Example 1, the components of Comparative Example 4 are exactly the same, and the API ratio of each drug-containing part is also consistent. The difference lies mainly in the preparation process. Specifically, in the process of co-grinding the API and the filler, the weight ratio of the API to the co-powdered filler is adjusted to 1:35. The specific formula is shown in Table 13:

[0152] Table 13. Comparative Example 4 Riociguat oral preparation formulation composition table

[0153]

[0154]

[0155] Comparative Example 5

[0156] This comparative example provides an oral preparation of riociguat. Compared with Example 1, the components and their weight proportions in this comparative example are exactly the same, and the only difference is the preparation process. Specifically, in the process of co-crushing the API and the co-powder filler, the co-crushing time is set to 20s.

[0157] Comparative Example 6

[0158] This comparative example provides an oral preparation of riociguat. Compared with Example 1, the only difference in this comparative example is that the sustained-release material in the drug-containing sustained-release portion is replaced by polyoxyethylene from hydroxypropyl methylcellulose K100M. In addition, the preparation process of Comparative Example 5 is the same as that of Example 1.

[0159] Comparative Example 7

[0160] This comparative example provides a riociguat oral preparation. Compared with Example 1, the difference of this comparative example is that the weight proportion of the sustained-release material (hydroxypropyl methylcellulose K100M) in the drug-containing sustained-release part is reduced to 15%. The specific formula is shown in Table 14:

[0161] Table 14. Comparative Example 7 Riociguat oral preparation formulation composition table

[0162]

[0163]

[0164] Preparation process: The preparation process of this comparative example is the same as that of Example 1.

[0165] Comparative Example 8

[0166] This comparative example provides a riociguat oral preparation. Compared with Example 1, the difference of this comparative example is that the weight proportion of the sustained-release material (hydroxypropyl methylcellulose K100M) in the drug-containing sustained-release part is increased to 45%. The specific formula is shown in Table 15:

[0167] Table 15. Comparative Example 8 Riociguat oral preparation formulation composition table

[0168]

[0169] Preparation process: The preparation process of this comparative example is the same as that of Example 1.

[0170] Comparative Example 9

[0171] This comparative example provides a riociguat oral preparation. Compared with Example 1, the formula and weight proportion of each component in this comparative example are exactly the same, and the only difference is that the disintegrant in the drug-containing immediate-release part and the drug-containing tablet core is replaced by pregelatinized starch instead of cross-linked polyvinylpyrrolidone.

[0172] Preparation process: The preparation process of this comparative example is the same as that of Example 1.

[0173] Comparative Example 10

[0174] This comparative example provides a riociguat oral preparation. Compared with Example 1, the formulation of this comparative example is exactly the same, and the main difference is that the weight proportion of the disintegrant (cross-linked polyvinylpyrrolidone) in the drug-containing immediate-release portion and the drug-containing tablet core is reduced to 2%. The specific formula is shown in Table 16:

[0175] Table 16. Comparative Example 10 Riociguat oral preparation formulation composition table

[0176]

[0177] Preparation process: The preparation process of this comparative example is the same as that of Example 1.

[0178] Test Case

[0179] Dissolution Testing

[0180] Dissolution conditions: 37°C ± 0.5°C, paddle method, 100 rpm, pH 6.8 + 0.5% SDS, 900 ml.

[0181] The qualified requirements for dissolution of Riociguat are shown in Table 17:

[0182] Table 17. Riociguat dissolution qualification standard table:

[0183] time 2h 12h 24h Dissolution % ≥35 75-85 ≥90

[0184] Table 18. Summary of dissolution rates at different times for Examples 1 and 2 and Comparative Examples 1 and 2

[0185]

[0186]

[0187] It can be seen from the test results in Table 18 that Comparative Example 1 lowers the content of riociguat in the drug-containing immediate-release part. At this time, the ratio of the API prescription amount in the drug-containing immediate-release part, the drug-containing sustained-release part, and the drug-containing tablet core of Comparative Example 1 is 1:10:1. Since the API ratio in the drug-containing sustained-release part is too high, the drug release rate decreases, resulting in a significant decrease in the dissolution rates of 2h, 12h, and 24h, which does not meet the qualified standard requirements in Table 17; Comparative Example 2 increases the content of riociguat in the drug-containing immediate-release part and the drug-containing tablet core. At this time, the ratio of the API prescription amount in the drug-containing immediate-release part, the drug-containing sustained-release part, and the drug-containing tablet core of Comparative Example 2 is 1:0.33:1. Since the API ratio in the drug-containing immediate-release part is too high, the drug release rate is accelerated, resulting in incomplete dissolution, causing a decrease in the dissolution rate within 24 hours, affecting the bioavailability of the preparation, and by examining the RSD values ​​of different batches, it is found that compared with Examples 1 and 2, the consistency of Comparative Example 2 is poor, and the product quality is unstable.

[0188] Table 19. Summary of dissolution rates at different times for Examples 1, 3, 4 and Comparative Examples 3, 4

[0189]

[0190] According to the test results in Table 19, the ratio of riociguat to the co-powder filler in Comparative Example 3 was increased to 1:3. With the same co-powder time of 45 seconds, the dissolution rates at the three time points of 2 hours, 12 hours and 24 hours all decreased significantly. Moreover, in the repeatability test, the RSD values ​​of multiple tests of Comparative Example 3 increased significantly, indicating poor consistency, which may cause the quality of different batches of products to be uncontrollable. The ratio of riociguat to the co-powder filler in Comparative Example 4 was reduced to 1:35, which also resulted in a significant decrease in the dissolution rates at the two test points of 12 hours and 24 hours.

[0191] Table 20. Summary of dissolution at different times for Examples 1, 5, 6 and Comparative Example 5

[0192]

[0193]

[0194] It can be seen from the test results in Table 20 that in Comparative Example 5, the co-crushing time of riociguat and the co-powder filler was reduced, resulting in incomplete comminution of riociguat, causing the dissolution rates at the three test points of 2h, 12h and 24h to decrease, especially the dissolution rate at the 24h test point could no longer meet the qualified standard requirements shown in Table 17.

[0195] Table 21. Summary of dissolution at different times for Examples 1, 7 and Comparative Example 6

[0196] Example 1 Example 7 Comparative Example 6 Time (h) Average cumulative dissolution (%) Average cumulative dissolution (%) Average cumulative dissolution (%) 0 0.0 0.0 0.0 0.5 29.3 28.3 24.9 1 35.1 36.3 31.3 2 40.1 41.0 35.9 4 48.9 49.3 44.8 6 57.8 58.7 51.9 8 65.9 66.8 60.0 12 80.3 81.4 72.0 16 90.5 91.8 77.2 20 96.7 98.1 82.8 24 99.8 99.9 87.0

[0197] From the test results in Table 21, it can be seen that in Comparative Example 6, polyoxyethylene is used as the sustained-release material of the drug-containing sustained-release part. At the same 30% weight ratio of addition, the solubility at each test point decreases, especially the solubility at 12h and 24h no longer meets the qualified standard requirements.

[0198] Table 22. Summary of dissolution at different times for Examples 1, 8, 9 and Comparative Examples 7 and 8

[0199]

[0200] From the test results in Table 22, it can be seen that in Example 7, the buffer material content was lowered, resulting in an increase in the dissolution rate at each time point, especially the dissolution rate at 12h exceeded the qualified standard requirements; in Example 8, the buffer material content was increased, resulting in a decrease in the dissolution rate at each time point, especially the dissolution rates at 12h and 24h were both lower than the qualified standard requirements.

[0201] Table 23. Summary of dissolution rates at different times for Examples 1, 10-12 and Comparative Examples 9 and 10

[0202]

[0203]

[0204] From the test results in Table 23, it can be seen that in Comparative Example 9, pregelatinized starch was used as the disintegrant for the drug-containing immediate-release portion and the drug-containing tablet core, resulting in a decrease in the dissolution rate at each test time point, especially the dissolution rates at 2h and 24h were both lower than the qualified standard requirements; in Comparative Example 10, the disintegrant content of the drug-containing immediate-release portion and the drug-containing tablet core was reduced to 2%, which also resulted in a decrease in the dissolution rate at each test time point, among which the dissolution rates at the three test points of 2h, 12h and 24h were all lower than the qualified standard requirements.

[0205] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the technical solution of the present invention, and are not intended to limit the specific implementation methods of the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the claims of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A riociguat oral preparation, characterized in that: The medicine-containing shell comprises a medicine-containing tablet core, wherein the medicine-containing shell completely encapsulates the medicine-containing tablet core, or the medicine-containing tablet core is embedded in the medicine-containing shell and a part of the medicine-containing tablet core is exposed on the surface of the medicine-containing shell; The drug-containing shell includes a drug-containing immediate-release portion and a drug-containing sustained-release portion, wherein the components of the drug-containing immediate-release portion include: a first riociguat active ingredient, a first filler, a first disintegrant, a first binder, a first solubilizing agent, and a first lubricant; the components of the drug-containing sustained-release portion include: a second riociguat active ingredient, a second filler, a second binder, a second solubilizing agent, a second lubricant, a sustained-release material, and a glidant; The drug-containing tablet core comprises a drug-containing inner core and a coating outer layer, wherein the coating outer layer covers the drug-containing inner core; the components of the drug-containing inner core comprise: a third riociguat active ingredient, a third filler, a second disintegrant, a third binder, a third cosolvent and a third lubricant.

2. The riociguat oral preparation according to claim 1, characterized in that In terms of weight percentage, the content of the first riociguat active ingredient in the drug-containing immediate-release portion is 0.2-2%; and / or, The content of the second riociguat active ingredient in the drug-containing sustained-release portion is 0.2-2%; and / or, The content of the third riociguat active ingredient in the drug-containing core is 0.2-2%.

3. The riociguat oral preparation according to claim 1, characterized in that The weight ratio of the first riociguat active ingredient, the second riociguat active ingredient, and the third riociguat active ingredient is (0.8-1.2):(2-6):(0.8-1.2).

4. The riociguat oral preparation according to claim 1, characterized in that The coating outer layer comprises an isolation coating layer and an enteric coating layer, and the isolation coating layer and the enteric coating layer are coated on the surface of the drug-containing inner core from the inside to the outside; preferably, the ratio of the weight of the isolation coating layer to the weight of the drug-containing inner core is (2-5):100, and the ratio of the weight of the enteric coating to the weight of the drug-containing inner core is (8-12):100; and / or, It also includes a film coating layer, the film coating layer is coated on the surface of the drug-containing shell; and / or, The first filler, the second filler or the third filler is selected from any one or more of lactose, microcrystalline cellulose, mannitol, starch or pregelatinized starch; and / or, The first disintegrant or the second disintegrant is selected from any one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and partially pregelatinized starch; and / or, The first binder, the second binder or the third binder is selected from any one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl methylcellulose or hydroxypropyl cellulose; and / or, The first cosolvent, the second cosolvent or the third cosolvent is selected from any one or more of Tween-80, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene-polyoxypropylene copolymers, glycerol, sodium stearate, calcium stearate, sodium lauryl sulfate, and fatty acid glycerides; and / or, The first lubricant, the second lubricant or the third lubricant is selected from any one of talc, hydrogenated vegetable oil, sodium stearyl fumarate or magnesium stearate; and / or, The sustained-release material is selected from any one or more of hydroxypropylmethylcellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate, carbomer or polyethylene oxide; and / or, The glidant is selected from colloidal silicon dioxide or talc.

5. The riociguat oral preparation according to any one of claims 1 to 4, characterized in that The drug-containing rapid-release portion includes the following components in parts by weight: First, 0.2-2 parts of the active ingredient of riociguat; 3-10 parts of the first disintegrant; 75-95 parts of the first filler; 1-10 parts of the first adhesive; 0.2-3 parts of the first lubricant; The first co-solvent is 0.02-0.2 parts.

6. The riociguat oral preparation according to any one of claims 1 to 4, characterized in that The drug-containing sustained-release portion includes the following components in parts by weight: The second riociguat active ingredient 0.2-2 parts; The content of the second filler is 55-75 parts; The content of the second adhesive is 1-10 parts; The content of the second lubricant is 0.2-3 parts; The second co-solvent content is 0.02-0.5 parts; The content of sustained-release material is 20-40 parts; The content of the flow aid is 0.2-3 parts.

7. The riociguat oral preparation according to any one of claims 1 to 4, characterized in that The drug-containing tablet core comprises the following components in parts by weight: The third riociguat active ingredient 0.2-2 parts; The content of the second disintegrant is 3-10 parts; 75-95 parts of the third filler; 1-10 parts of the third adhesive; The third lubricant 0.2-3 parts; The third co-solvent is 0.02-0.5 parts.

8. A method for preparing the riociguat oral preparation according to any one of claims 1 to 7, characterized in that: The steps include: The first riociguat active ingredient, the first filler, the first disintegrant, the first binder, the first solubilizer and the first lubricant are wet granulated to obtain drug-containing immediate-release granules; the second riociguat active ingredient, the second filler, the second binder, the second solubilizer, the second lubricant, the sustained-release material and the glidant are wet granulated to obtain drug-containing sustained-release granules; the third riociguat active ingredient, the third filler, the second disintegrant, the third binder, the third solubilizer and the third lubricant are wet granulated and then tableted to obtain the drug-containing inner core, and the drug-containing inner core is coated with the coating outer layer to obtain the drug-containing tablet core; The drug-containing immediate-release granules, the drug-containing sustained-release granules and the drug-containing tablet core are mixed and compressed into tablets, and then subjected to a coating process to obtain the riociguat oral preparation, wherein the drug-containing immediate-release granules form the drug-containing immediate-release part, and the drug-containing sustained-release granules form the drug-containing sustained-release part.

9. The method according to claim 8, characterized in that The first filler includes a first main filler and a first co-powder filler. In the process of preparing the drug-containing immediate-release granules, the first riociguat active ingredient and the first co-powder filler are mixed in advance and then co-crushed to obtain a first riociguat co-crushed mixture, which is then wet granulated; and / or, The second filler includes a second main filler and a second co-powder filler. In the process of preparing the drug-containing sustained-release granules, the second riociguat active ingredient and the second co-powder filler are mixed in advance and then co-crushed to obtain a second riociguat co-crushed mixture, which is then wet granulated; and / or, The third filler includes a third main filler and a third co-powder filler. In the process of preparing the drug-containing inner core, the third riociguat active ingredient and the third co-powder filler are mixed in advance and then co-crushed to obtain a third riociguat co-crushed mixture, which is then wet granulated.

10. The method according to claim 9, characterized in that The ratio of the first riociguat active ingredient to the first co-powder filler is 1:5 to 1:30 by weight; and / or, The ratio of the second riociguat active ingredient to the second co-powder filler is 1:5 to 1:30; and / or, The ratio of the third riociguat active ingredient to the third co-powder filler is 1:5 to 1:30; and / or, The co-crushing time of the first riociguat active ingredient and the first co-powder filler is 30s to 60s; and / or, The co-crushing time of the second riociguat active ingredient and the second co-powder filler is 30s to 60s; and / or, The co-crushing time of the third riociguat active ingredient and the third co-powder filler is 30s to 60s.

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