Riociguat solid dispersion composition, sustained-release composition, and preparation method and application of riociguat solid dispersion composition and sustained-release composition

Abstract

The invention belongs to the technical field of medicines, and relates to a riociguat solid dispersion composition, a riociguat sustained-release composition and a preparation method and application thereof. The riociguat solid dispersion composition is prepared from riociguat and a carrier material, the carrier material is selected from one or more of copovidone, a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer, hydroxypropyl methylcellulose acetate succinate, polyethylene glycol and hydroxy propyl cellulose. The riociguat is prepared into a solid dispersion form, the solubility of the raw material medicine can be remarkably improved, the dissolution end point is improved, meanwhile, the absorption of the raw material medicine in a body is improved, and the riociguat solid dispersion has a very good slow-release effect and is more suitable for treating pulmonary arterial hypertension.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a riociguat solid dispersion composition, a sustained-release composition, and a preparation method and application thereof. Background Art

[0002] Riociguat, chemical name 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidine(methyl)carbamate, chemical structure shown in Formula I, is a soluble guanylate cyclase (sGC) agonist. sGC is an enzyme in the cardiopulmonary system and a nitric oxide receptor. The drug is suitable for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH).

[0003]

[0004] For the complex disease of pulmonary arterial hypertension (PAH), maintaining a stable blood drug concentration is crucial for patient tolerance and drug efficacy. However, Riociguat is currently available only in the form of ordinary tablets on the market, and its dosage guide recommends starting with 1 mg three times a day, followed by an increase of 0.5 mg every two weeks until the maximum recommended dose of 2.5 mg three times a day is reached. This incremental strategy aims to gradually adjust to the optimal individualized dose to maximize the therapeutic effect.

[0005] However, the existing riociguat tablets have large fluctuations in blood drug concentration, and patients may miss doses, which may have an adverse effect on the stable control of the disease. In addition, many side effects of riociguat, such as gastrointestinal side effects and hypotension, may be related to blood drug concentration. Therefore, it is particularly important for patients to find a more stable and reliable drug release form to reduce blood drug concentration fluctuations and the risk of missed doses.

[0006] Chinese invention patent application CN117771199A discloses a riociguat sustained-release tablet and a preparation method thereof, comprising the following components in percentage by mass: 1.5-7.5% riociguat, 40-50% filler, 30-45% sustained-release matrix, 3-5% binder, 3-4% disintegrant, 1-1.5% lubricant and 3.0-4.0% coating powder, and the hydration rate, swelling or diffusion rate of the tablets are controlled by the combination of the components, thereby controlling the drug release rate to achieve a sustained-release effect. However, the problem of limited absorption in the rear end of the intestine of riociguat as a poorly soluble drug is not solved, and it is expected that the bioavailability of the drug is limited and the sustained-release effect cannot be truly achieved.

[0007] Chinese invention patent application CN106913554A discloses a method for preparing a preparation for treating pulmonary arterial hypertension. Riociguat is micronized to achieve particle size control, thereby achieving effective dissolution of the drug. However, the dissolution rate of the tablet reaches more than 95% in 30 minutes, which is contrary to the requirements of riociguat for stable release, reducing the number of medications, and avoiding missed doses.

[0008] In view of the characteristics of 24-hour sustained-release preparations, although the traditional riociguat sustained-release tablets can prolong the time for the drug to reach the maximum blood concentration (T max ), but they have not solved the problem of drug absorption difficulties in the small intestine, which also hinders the possibility of preparing 24-hour long-acting sustained-release preparations. Therefore, how to achieve a balance between the adequate dissolution of riociguat and the sustained-release effect and ensure that the drug can be effectively absorbed locally in the intestine is still a major problem to be solved in the preparation of riociguat preparations. Summary of the invention

[0009] The present invention aims at the problems existing in the prior art, and provides a riociguat solid dispersion composition, a sustained-release composition, and a preparation method and application thereof. By preparing riociguat and a carrier material into a solid dispersion form, it is ensured that the drug can maintain a sufficient absorption amount in the rear end of the intestine, improve the dissolution endpoint, and have a significant sustained-release effect.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] The present invention provides a riociguat solid dispersion composition, comprising: riociguat and a carrier material; the carrier material is selected from one or more of copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose acetate succinate, polyethylene glycol and hydroxypropyl cellulose.

[0012] Furthermore, the riociguat is in the form of amorphous or microcrystalline particles with a particle size D 90 ≤20μm.

[0013] In the present invention, the Riociguat API may exist in any form (amorphous or crystalline), wherein the crystalline form preferably has a particle size of D 90 The particle size is ≤20μm, and the particle size can be achieved by various means, such as nano-grinding, micronization or eutectic technology.

[0014] Furthermore, the solid dispersion is prepared by hot melt extrusion or dry spraying.

[0015] The present invention also provides a riociguat sustained-release composition, which is composed of the above-mentioned riociguat solid dispersion and excipients, wherein the excipients include one or more of a sustained-release material, a filler, a lubricant and a surfactant.

[0016] Furthermore, the composition comprises, by mass percentage, 1-10% riociguat, 2.5-35% carrier material, 10-60% sustained-release material, 25.5-75.5% filler, 0-5% lubricant and 0-5% surfactant.

[0017] Preferably, the composition comprises, by mass percentage, 1-2.5% riociguat, 4-10% carrier material, 30-50% sustained-release material, 40-50% filler, 0.5-1% lubricant and 0.5-1% surfactant.

[0018] Furthermore, the mass ratio of riociguat to the carrier material is 1:2-14.

[0019] Furthermore, the sustained-release material is selected from one or more of hydroxypropyl methylcellulose, ethyl cellulose and povidone; the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, starch, pregelatinized starch, mannitol and sorbitol; the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, hard sodium fumarate, hydrogenated vegetable oil and behenic acid glyceryl ester; the surfactant is selected from one or more of sodium lauryl sulfate, sodium lauryl sulfate, glycerol and monostearate glyceryl ester.

[0020] Preferably, the sustained-release material is hypromellose; the filler is microcrystalline cellulose and lactose monohydrate; and the lubricant is magnesium stearate.

[0021] The present invention also provides a method for preparing a riociguat sustained-release composition, comprising the following steps:

[0022] (1) taking the raw material riociguat, adding the carrier material, and mixing evenly;

[0023] (2) adding the mixed materials into a hot melt extruder, setting the processing temperature to 100° C.-220° C. and the screw speed to 100-500 rpm, and crushing and sieving after extrusion to obtain a solid dispersion;

[0024] (3) Taking a sustained-release material, a filler, a lubricant and / or a surfactant, and mixing them evenly with the above solid dispersion to obtain a solid dispersion.

[0025] The present invention also provides another method for preparing a riociguat sustained-release composition, comprising the following steps:

[0026] (1) dissolving the above-mentioned riociguat and carrier material in an organic solvent to obtain a solution;

[0027] (2) using a spray dryer with an inlet temperature of 60-80° C., an outlet temperature of 40-50° C., and an atomization pressure of 0.1-0.5 MPa to spray dry the solution to obtain a solid dispersion;

[0028] (3) Taking a sustained-release material, a filler, a lubricant and / or a surfactant, and mixing them evenly with the above solid dispersion to obtain a solid dispersion.

[0029] The present invention also provides use of the riociguat solid dispersion, the riociguat sustained-release composition, or the riociguat sustained-release composition prepared by the above-mentioned preparation method in the preparation of a drug for treating pulmonary arterial hypertension.

[0030] Furthermore, the pulmonary arterial hypertension drug dosage form is any one of sustained-release granules, sustained-release tablets and sustained-release capsules.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The present invention prepares riociguat and a carrier material into a solid dispersion, which effectively improves the solubility of the raw material drug compared to the common sustained-release prescription, and the sustained-release preparation containing the riociguat solid dispersion also has excellent dissolution performance; at the same time, it can also ensure that the drug can be effectively absorbed locally in the intestine, that is, it can maintain a sufficient absorption amount in the rear end of the intestine, thereby significantly improving the bioavailability of the drug and solving the problem of difficult absorption of the drug in the small intestine; in addition, compared with the common sustained-release prescription and the acid-added improved prescription, the sustained-release preparation containing the riociguat solid dispersion can prolong the time (T ) for the drug to reach the maximum blood drug concentration to a greater extent. max ), with excellent sustained-release effect.

[0033] In addition, the solid dispersion in the riociguat sustained-release preparation of the present invention can be prepared by hot-melt extrusion, spray drying, etc., and the preparation methods are diverse and can be applied to various production conditions. After the API and the carrier material are prepared into a solid dispersion, the dissolution effect, in vivo absorption effect and sustained-release effect are almost unaffected by changes in the type and amount of excipients. For example, in any sustained-release material and any sustained-release material composition ratio, the drug dissolution effect is significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The pharmacokinetic curves of part of the prescriptions of Example 1 and Example 2 of the present invention and the original tablets are shown. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are 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 creative work are within the scope of protection of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The following is an exemplary description:

[0036] Riociguat, particle size D 90 ≤20μm;

[0037] Copolyvidone was purchased from BASF with a molecular weight of 45,000-70,000.

[0038] Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was purchased from Ashland, with a viscosity K value of 25.2-30.8;

[0039] Hydroxypropyl cellulose HME was purchased from DuPont;

[0040] Hydroxypropyl cellulose K4M and hydroxypropyl cellulose K100LV were purchased from Ashland;

[0041] Hydroxypropyl methylcellulose acetate succinate was purchased from Shin-Etsu Co., Ltd. of Japan, with a viscosity of 2.4-3.6 mPa*s.

[0042] Example 1

[0043] Riociguat sustained-release tablets were prepared according to the prescription in Table 1. The specific preparation method was as follows: weigh the raw and auxiliary materials in the prescribed amount, mix the raw and auxiliary materials evenly, and press the tablets (tablet weight was about 300 mg).

[0044] Table 1

[0045]

[0046]

[0047] Test Example 1

[0048] According to the dissolution and release determination method (General Rules 0931 of Part IV of the 2020 Edition of the Chinese Pharmacopoeia), the second method (paddle method) was selected as the dissolution method; the paddle method speed was 50 rpm, and the dissolution medium was a phosphate solution with a pH of 6.8. The results are shown in Table 2.

[0049] Table 2

[0050]

[0051] The API (riociguat) of this product is a poorly soluble drug. The conventional sustained-release prescription 1-1 could not be completely dissolved in a pH 6.8 solution after 12 hours due to limited solubility. The addition of tartaric acid to prescription 1-2 had some improvement, but the effect was not obvious; prescriptions 1-3 to 1-6 were prepared by directly mixing API and solid dispersion carrier materials and tableting, but no solid dispersion was formed and no obvious improvement effect was found.

[0052] Example 2

[0053] Riociguat sustained-release tablets were prepared according to prescription 2-1 in Table 3. The specific preparation method is as follows:

[0054] (1) Take the prescribed amount of raw material riociguat, pass it through a 40-mesh sieve, add the prescribed amount of carrier material, and mix well;

[0055] (2) Add the mixed materials into the hot melt machine, preset the heating module temperature according to the material properties: 100°C, 130°C, 160°C, 200°C, 200°C, 200°C, 200°C, 200°C, and the screw speed is 200rpm. Adjust the parameters according to the material state; crush after extrusion, and pass through a 20-mesh sieve;

[0056] (3) Take the remaining excipients in the prescription amount, mix them evenly with the above-mentioned crushed extrudate, and use a rotary tablet press to compress the tablets with a hardness of about 8 kg (tablet weight of about 300 mg).

[0057] Riociguat sustained-release tablets were prepared according to prescription 2-2 in Table 3. The specific preparation method is as follows:

[0058] (1) Take the prescribed amount of raw material riociguat, pass it through a 40-mesh sieve, add the prescribed amount of carrier material, and mix well;

[0059] (2) Add the mixed materials into the hot melt machine, preset the heating module temperature according to the material properties: 110°C, 140°C, 170°C, 210°C, 210°C, 210°C, 210°C, 210°C, and the screw speed is 200 rpm. Adjust the parameters according to the material state; crush after extrusion, and pass through a 20-mesh sieve;

[0060] (3) Take the remaining auxiliary materials in the prescription amount, mix them evenly with the above-mentioned crushed extrudate, and use a rotary tablet press to compress the tablets with a hardness of about 8 kg (tablet weight of about 300 mg).

[0061] Riociguat sustained-release tablets were prepared according to prescription 2-3 in Table 3. The specific preparation method is as follows:

[0062] (1) Take the prescribed amount of raw material riociguat, pass it through a 40-mesh sieve, add the prescribed amount of carrier material, and mix well;

[0063] (2) Add the mixed materials into the hot melt machine, and preset the heating module temperature according to the material properties: 110°C, 140°C, 170°C, 220°C, 220°C, 220°C, 220°C, 220°C, and the screw speed is 100 rpm. Adjust the parameters according to the material state; crush after extrusion, and pass through a 20-mesh sieve;

[0064] (3) Take the remaining auxiliary materials in the prescription amount, mix them evenly with the above-mentioned crushed extrudate, and use a rotary tablet press to compress the tablets with a hardness of about 8 kg (tablet weight of about 300 mg).

[0065] Riociguat sustained-release tablets were prepared according to prescription 2-4 in Table 3. The specific preparation method is as follows:

[0066] (1) Take the prescribed amount of raw material riociguat, pass it through a 40-mesh sieve, add the prescribed amount of carrier material, and mix well;

[0067] (2) Add the mixed materials into the hot melt machine, and preset the heating module temperatures according to the material properties: 110°C, 140°C, 170°C, 220°C, 220°C, 220°C, 220°C, 220°C, and the screw speed is 200rpm. Adjust the parameters according to the material state; crush after extrusion, and pass through a 20-mesh sieve;

[0068] (3) Take the remaining auxiliary materials in the prescription amount, mix them evenly with the above-mentioned crushed extrudate, and use a rotary tablet press to compress the tablets with a hardness of about 8 kg (tablet weight of about 300 mg).

[0069] Riociguat sustained-release tablets were prepared according to prescription 2-5 in Table 3. The specific preparation method is as follows:

[0070] (1) Take the prescribed amount of raw material riociguat, pass it through a 40-mesh sieve, add the prescribed amount of carrier material, and mix well;

[0071] (2) Add the mixed materials into the hot melt machine, and preset the heating module temperatures according to the material properties: 100°C, 120°C, 150°C, 180°C, 180°C, 180°C, 180°C, 180°C, and 180°C. The screw speed is 500 rpm, and the parameters are adjusted according to the material state; crush after extrusion, and pass through a 20-mesh sieve;

[0072] (3) Take the remaining auxiliary materials in the prescription amount, mix them evenly with the above-mentioned crushed extrudate, and use a rotary tablet press to compress the tablets with a hardness of about 8 kg (tablet weight of about 300 mg).

[0073] Table 3

[0074]

[0075]

[0076] Test Example 2

[0077] The dissolution of the above formulation was tested using the same test method as in Test Example 1. The results are shown in Table 4.

[0078] Table 4

[0079]

[0080] It can be seen from the above table that compared with Prescriptions 1-3 to 1-6, the dissolution effect of Prescriptions 2-1 to 2-5 was significantly improved after the active ingredients and carrier materials were prepared into a solid dispersion form by hot melt extrusion.

[0081] Example 3

[0082] Riociguat sustained-release tablets were prepared according to the prescription in Table 5. The specific preparation method is as follows:

[0083] (1) Take the prescribed amount of raw material riociguat, pass it through a 40-mesh sieve, and set aside;

[0084] (2) Dissolving riociguat and the carrier material in acetone to obtain a solution (note: the amount of acetone is not specifically limited, as long as riociguat and the carrier material are completely dissolved);

[0085] (3) using a spray dryer with an inlet temperature of 65° C., an outlet temperature of 45° C., and an atomization pressure of 0.2 MPa to atomize the above solution; drying the spray-dried sample in a vacuum drying oven at 50° C. for at least 2 hours;

[0086] (4) Take the remaining excipients in the prescription amount, mix them evenly with the above-mentioned crushed extrudate, and use a rotary tablet press to compress the tablets with a hardness of 8 kg (tablet weight is about 300 mg).

[0087] Table 5

[0088]

[0089] Test Example 3

[0090] The dissolution of the above formulation was tested using the same test method as in Test Example 1. The results are shown in Table 6.

[0091] Table 6

[0092]

[0093] It can be seen from the above table that compared with prescriptions 1-3 to 1-6, the dissolution effect of prescriptions 3-1 to 3-2 was also significantly improved after the active ingredient and the carrier material were prepared into a solid dispersion form by spray drying;

[0094] In general, the present invention prepares the active ingredient and the carrier material into a solid dispersion form. Whether the solid dispersion is prepared by hot melt extrusion or spray drying, there is no significant difference in the dissolution effect, and the improvement of the dissolution effect is not limited by the preparation process.

[0095] Example 4

[0096] Riociguat sustained-release tablets were prepared according to the prescription in Table 7. The preparation method was the same as that of prescription 2-1 in Example 2 (hot melt extrusion, tablet weight of about 300 mg).

[0097] Table 7

[0098]

[0099] Test Example 4

[0100] The dissolution of the above formulation was tested using the same test method as in Test Example 1. The results are shown in Table 8.

[0101] Table 8

[0102]

[0103] It can be seen from the above table that the sustained-release preparation prepared by further combining the solid dispersion material of the present invention with a sustained-release material is not limited by the sustained-release material and has the effect of significantly improving the dissolution of poorly soluble drugs in any sustained-release material.

[0104] Example 5

[0105] Riociguat sustained-release tablets were prepared according to the prescription in Table 9, and the preparation method was the same as that of prescription 2-1 in Example 2 (hot melt extrusion, tablet weight of about 300 mg).

[0106] Table 9

[0107]

[0108]

[0109] Test Example 5

[0110] The dissolution of the above formulation was tested using the same test method as in Test Example 1. The results are shown in Table 10.

[0111] Table 10

[0112]

[0113] It can be seen from the above table that the dissolution effects of prescriptions 5-2 to 5-4 are better, so the ratio of API to carrier material is preferably 1:2-14.

[0114] Example 6

[0115] Riociguat sustained-release tablets were prepared according to the prescription in Table 11, and the preparation method was the same as that of prescription 2-1 in Example 2 (hot melt extrusion, tablet weight about 300 mg).

[0116] Table 11

[0117]

[0118]

[0119] Test Example 5

[0120] The dissolution of the above formulation was tested using the same test method as in Test Example 1. The results are shown in Table 12.

[0121] Table 12

[0122]

[0123] It can be seen from the above table that the sustained-release material in the sustained-release preparation of the present invention can achieve excellent dissolution effect within the above-mentioned ratio range.

[0124] Example 7

[0125] Riociguat sustained-release tablets were prepared according to the prescription in Table 13, and the preparation method was the same as that of prescription 2-1 in Example 2 (hot melt extrusion, tablet weight about 300 mg).

[0126] Table 13

[0127]

[0128]

[0129] Test Example 7

[0130] The dissolution of the above formulation was tested using the same test method as in Test Example 1. The results are shown in Table 14.

[0131] Table 14

[0132]

[0133] It can be seen from the above table that the sustained-release preparation of the present invention can achieve excellent dissolution effect when the mass percentage of API in the preparation is within the range of 1-10%.

[0134] Test Example 8: Study on the absorption kinetics of riociguat sustained-release preparation

[0135] Pharmacokinetic evaluation was performed on 4 beagle dogs. The 4 beagle dogs were orally administered 3 mg of each of the test preparations 1-1, 1-2, 1-3, and 2-1, as well as 1 mg of the reference preparation. There was at least a 7-day interval between each dose. The blood drug concentration of each dog was measured at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after each dose. Based on the above data, the average blood drug concentration of the 4 beagle dogs was calculated, and the pharmacokinetic curve was drawn. The results are shown in Figure 1 At the same time, the pharmacokinetic characteristic parameters of the drug were calculated according to the pharmacokinetic curve. The results are shown in Table 15.

[0136] Table 15

[0137] Prescription Number Specification <![CDATA[T max (h)]]> <![CDATA[C max (ng / mL)]]> <![CDATA[AUC 0-24h (mg / mL)]]> Prescription 1-1 3mg 2.0 202.4 1122.7 Prescription 1-3 3mg 2.0 142.3 945.3 Prescription 2-1 3mg 2.0 141.7 1124.1 Prescription 2-4 3mg 4.5 136.8 1719.9 Original tablets (Bio-Angio) 1mg 0.9 133.8 585.3

[0138] As can be seen from the table above, when the API and carrier materials are prepared into a solid dispersion sustained-release preparation, the drug can maintain sufficient absorption in the posterior end of the intestine, thereby significantly improving the absorption amount AUC 0-24h , and can effectively prolong the time it takes for the drug to reach its maximum blood concentration (T max ), producing a sustained-release effect.

[0139] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A riociguat solid dispersion composition, characterized in that: The riociguat solid dispersion composition comprises: riociguat and a carrier material; the carrier material is selected from one or more of copovidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methylcellulose acetate succinate, polyethylene glycol and hydroxypropyl cellulose.

2. The riociguat solid dispersion composition according to claim 1, characterized in that The riociguat is in amorphous or microcrystalline form. When in microcrystalline form, the particle size D 90 ≤20μm.

3. The riociguat solid dispersion composition according to claim 1, characterized in that The solid dispersion is prepared by hot melt extrusion or spray drying.

4. A riociguat sustained-release composition, characterized in that: It is composed of the riociguat solid dispersion according to any one of claims 1 to 3 and excipients; the excipients include one or more of a sustained-release material, a filler, a lubricant and a surfactant.

5. The riociguat sustained-release composition according to claim 4, characterized in that The composition comprises, by mass percentage, 1-10% riociguat, 2.5-35% carrier material, 10-60% sustained-release material, 25.5-75.5% filler, 0-5% lubricant, and 0-5% surfactant; preferably, the composition comprises, by mass percentage, 1-2.5% riociguat, 4-10% carrier material, 30-40% sustained-release material, 45-55% filler, 0.5-1% lubricant, and 0-1% surfactant.

6. The riociguat sustained-release composition according to claim 5, characterized in that The mass ratio of riociguat to the carrier material is 1:2-14.

7. The riociguat sustained-release composition according to claim 4, characterized in that: The sustained-release material is selected from one or more of hydroxypropyl methylcellulose, ethyl cellulose and povidone; the filler is selected from one or more of microcrystalline cellulose, lactose monohydrate, starch, pregelatinized starch, mannitol and sorbitol; the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, hard sodium fumarate, hydrogenated vegetable oil and glyceryl behenate; the surfactant is selected from one or more of sodium lauryl sulfate, sodium lauryl sulfate, glycerol and glyceryl monostearate; preferably, the sustained-release material is hydroxypropyl methylcellulose; the filler is microcrystalline cellulose and lactose monohydrate; the surfactant is sodium lauryl sulfate; and the lubricant is magnesium stearate.

8. The method for preparing the riociguat sustained-release composition according to any one of claims 5 to 7, characterized in that: The following steps are involved: (1) taking the raw material riociguat, adding the carrier material, and mixing evenly; (2) adding the mixed materials into a hot melt extruder, setting the processing temperature to 100° C.-220° C. and the screw speed to 100-500 rpm, and crushing and sieving after extrusion to obtain a solid dispersion; (3) Taking a sustained-release material, a filler, a lubricant and / or a surfactant, and mixing them evenly with the above solid dispersion to obtain a solid dispersion.

9. The method for preparing the riociguat sustained-release composition according to any one of claims 5 to 7, characterized in that: The following steps are involved: (1) dissolving the above-mentioned riociguat and carrier material in an organic solvent to obtain a solution; (2) using a spray dryer with an inlet temperature of 60-80° C., an outlet temperature of 40-50° C., and an atomization pressure of 0.1-0.5 MPa to spray dry the solution to obtain a solid dispersion; (3) Taking a sustained-release material, a filler, a lubricant and / or a surfactant, and mixing them evenly with the above solid dispersion to obtain a solid dispersion.

10. Use of a riociguat solid dispersion or a riociguat sustained-release composition in the preparation of a drug for treating pulmonary hypertension, characterized in that: The riociguat solid dispersion is the riociguat solid dispersion according to any one of claims 1 to 3; the riociguat sustained-release composition is the riociguat sustained-release composition according to any one of claims 4 to 7 or the riociguat sustained-release composition prepared by the preparation method according to claim 8 or 9.

11. The use according to claim 10, characterized in that: The pulmonary arterial hypertension drug dosage form is any one of sustained-release granules, sustained-release tablets and sustained-release capsules.

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