Tadalafil and fasudil pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention provides a tadalafil and fasudil pharmaceutical composition as well as a preparation method and application thereof, and belongs to the technical field of preparation of pharmaceutical preparations. Through research, the applicant finds that when the tadalafil and the fasudil are combined for treating the pulmonary arterial hypertension, a synergistic effect can be generated, and the improvement effect is superior to that of single use of one of the medicines. Moreover, the invention provides a preparation process of a tablet of the pharmaceutical composition, and the tablet comprises the following components: 1-5% of tadalafil, 10-25% of fasudil, 60-75% of a filler, 1-4% of an adhesive, 5-8% of a disintegrating agent, 0.5-2.0% of a lubricant and 0.1-0.5% of a solubilizer. According to the preparation process, auxiliary materials are cheap and easy to obtain, the process is simple, large-scale production is easy, the prepared pharmaceutical composition is an oral tablet, and the problems that the fasudil injection is inconvenient to take and the solution is easy to degrade under illumination are solved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparation, and specifically relates to a tadalafil and fasudil pharmaceutical composition, a preparation method thereof, and an application thereof. Background Art

[0002] Pulmonary arterial hypertension (PAH) is a class of diseases characterized by pulmonary vascular remodeling, progressive elevation of pulmonary artery pressure and pulmonary vascular load. If not treated in time, with the progression of the disease, it can ultimately lead to refractory right heart failure and even death, and is a class of malignant cardiovascular diseases. PAH has a high incidence, lethality and mortality rate. Any factor that can cause an increase in pulmonary venous pressure, pulmonary blood flow, and pulmonary vascular resistance can lead to pulmonary arterial hypertension. Currently, 75% of patients with pulmonary arterial hypertension die within 5 years after diagnosis. The average survival period after the appearance of symptoms is 1.9 years, and the average survival time of those with right heart failure is less than 1 year.

[0003] Currently, the main principle of treating pulmonary arterial hypertension is to dilate blood vessels to make blood flow smooth. There are mainly three categories of clinical drugs: prostaglandins, such as alprostadil, which are generally only used during critical illness; endothelin receptor antagonists, such as bosentan and ambrisentan, which are also used to treat heart failure; phosphodiesterase-5 inhibitors, such as tadalafil and sildenafil.

[0004] Tadalafil [6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl, (6R,12aR)pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione] is a selective reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5), with a molecular weight of 389.404 and a molecular formula of C 22 H 19 N3O4, and the structural formula is as follows:

[0005]

[0006] Currently, the manufacturer of tadalafil tablets on the domestic market is Eli Lilly of the United States. The specifications are 2.5 mg, 5 mg, 10 mg, and 20 mg. This product was approved for listing in the European Union in 2002 and in the United States in 2003, with the trade name It then obtained the qualification to enter the Chinese market in 2005, with the trade name The indications are erectile dysfunction (ED) and erectile dysfunction (ED) combined with benign prostatic hyperplasia (BPH). Tadalafil can prevent the degradation of cGMP by inhibiting PDE-5, increase the intracellular concentration of cGMP, and cause vasodilation. Since PDE-5 is highly expressed in pulmonary vascular smooth muscle, tadalafil is also widely used clinically as an adjuvant drug for the treatment of pulmonary arterial hypertension. In 2009, tadalafil was approved by the FDA for the treatment of pulmonary arterial hypertension (PAH) classified as class 1 by the World Health Organization (WHO) clinically, that is, arterial pulmonary hypertension.

[0007] Fasudil hydrochloride [hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine] is a Rho kinase inhibitor and vasodilator with a molecular weight of 327.83 and a molecular formula of C 14 H 17 N3O2S·HCL, and the structural formula is as follows:

[0008]

[0009] Fasudil hydrochloride is a new drug with a wide range of pharmacological effects. It was first developed by Asahi Kasei Corporation of Japan and was first marketed in Japan in 1995. In 2001, China approved the import of Fasudil hydrochloride injection from Asahi Kasei Corporation of Japan, with the trade name "Elinalu", and the indications are ischemic cerebrovascular diseases caused by cerebral vasospasm after subarachnoid hemorrhage, etc. Fasudil hydrochloride is an isoquinoline sulfonamide derivative, which can not only inhibit the activity of intracellular free calcium ions, but also inhibit protein kinases A, G, C and myosin light chain kinase, that is, inhibit smooth muscle contraction, the phosphorylation of myosin light chain in the final stage, so that vascular smooth muscle relaxes and blood vessels dilate. At the same time, Fasudil hydrochloride is also a Rho kinase inhibitor. The Rho kinase pathway is one of the important pathogenic pathways leading to pulmonary artery contraction and pulmonary vascular remodeling in patients with pulmonary arterial hypertension. Fasudil can reduce the activity of Rho kinase, inhibit the contraction of pulmonary artery vascular smooth muscle, dilate pulmonary artery blood vessels, reduce pulmonary artery resistance, and reduce pulmonary artery pressure.

[0010] Patent CN113329751 mentions a drug combination of a PDE5 inhibitor and macitentan or apixantentan for the treatment and / or prevention of chronic thromboembolic pulmonary hypertension (CTEPH); Patent CN100367967 discloses a preparation method of an oral preparation of Fasudil hydrochloride; Patent CN102188433 mentions a compound preparation of Fasudil and beraprost and its preparation method and use for the treatment of pulmonary arterial hypertension.

[0011] There is no report on the combined use of fasudil and sildenafil for the treatment of pulmonary hypertension in patent and scientific literature searches. Given that there are already various treatment methods for pulmonary hypertension but no specific treatment, the present invention aims to provide a new pharmaceutically acceptable compound preparation of fasudil and tadalafil, which dilates blood vessels and synergistically treats pulmonary hypertension by simultaneously inhibiting Rho kinase and PDE5. The combined use of the two drugs is more effective in treating pulmonary hypertension than using them alone. Summary of the Invention

[0012] In view of the deficiencies of the prior art, the present invention provides a drug composition of tadalafil and fasudil, which contains the active drugs tadalafil and fasudil, as well as other pharmaceutically acceptable excipients, such as fillers, disintegrants, binders, solubilizers, lubricants, etc. The drug composition prepared by the present invention is an oral dosage form, which improves the inconvenient administration of fasudil injection and the problem of light instability of the solution; at the same time, the two play a synergistic role and have a better effect than using them alone. The present invention also provides a method for preparing tablets of the drug composition of tadalafil and fasudil. The preparation method of the present invention has a simple process, cheap and easily available excipients, and is easy to mass-produce.

[0013] The technical solution of the present invention is as follows:

[0014] A drug composition, wherein the composition uses tadalafil and fasudil as drug active ingredients, and the weight ratio of the two active ingredients of tadalafil and fasudil is 1:25 to 1:2 (w / w).

[0015] Further, the tadalafil can be the active ingredient itself or its pharmaceutically acceptable salt, and the fasudil can be its hydrochloride salt or other forms of pharmaceutically acceptable salts.

[0016] Further, the drug composition is a tablet, powder, liquid preparation, capsule, granule, aerosol inhalant or infusion.

[0017] In some embodiments of the present invention, the drug composition is a tablet, and in terms of mass percentage, it contains 1-5% tadalafil, 10-25% fasudil, and the balance is pharmaceutically acceptable excipients.

[0018] In some embodiments of the present invention, the drug composition is a tablet, and in terms of mass percentage, its component content is: 1-5% tadalafil, 10-25% fasudil, 60-75% filler, 1-4% binder, 5-8% disintegrant, 0.5-2.0% lubricant, 0.1-0.5% solubilizer.

[0019] In some embodiments of the present invention, the filler is selected from one or more of lactose, mannitol, microcrystalline cellulose, calcium hydrogen phosphate, and starch; the binder is selected from one or more of povidone, hypromellose, hydroxypropyl cellulose, ethyl cellulose, and sodium carboxymethyl cellulose; the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch, preferably croscarmellose sodium; the lubricant is selected from one or more of magnesium stearate, stearic acid, silicon dioxide, sodium stearyl fumarate, and talc; the solubilizer is selected from one or more of poloxamer, sodium lauryl sulfate, and Tween, preferably sodium lauryl sulfate.

[0020] Preferably, the filler is lactose or microcrystalline cellulose, the binder is hydroxypropyl cellulose or hypromellose, the disintegrant is croscarmellose sodium, the solubilizer is sodium lauryl sulfate, and the lubricant is magnesium stearate.

[0021] In some embodiments of the present invention, the preparation method of any of the above-mentioned pharmaceutical compositions comprises the following steps:

[0022] Step S1, premix tadalafil API with the filler, binder, and disintegrant;

[0023] Step S2, add the aqueous solution of the binder or purified water to the premix obtained in Step S1 and granulate using a granulator;

[0024] Step S3, screen the granules obtained in Step S2 and then dry;

[0025] Step S4, screen the dry granules obtained in Step S3 and then blend with the filler, disintegrant, and lubricant;

[0026] Step S5, premix fasudil API with the filler, binder, and disintegrant;

[0027] Step S6, add the aqueous solution of the binder or purified water to the premix obtained in Step S5 and granulate using a granulator;

[0028] Step S7, screen the granules prepared in Step S6 and then dry;

[0029] Step S8, screen the dry granules obtained in Step S7 and then blend with the disintegrant and lubricant;

[0030] Step S9, compress the total mixed granules obtained in Step S4 and Step S8 into bilayer tablets using a bilayer tablet press, or compress the total mixed granules obtained in Step S4 and Step S8 after mixing into monolayer tablets.

[0031] Use of any of the above-mentioned pharmaceutical compositions in the preparation of a medicament for treating pulmonary hypertension.

[0032] Compared with the prior art, the present invention has the following remarkable advantages:

[0033] (1) The pharmaceutical composition prepared by the present invention is an oral dosage form, which solves the problems of inconvenient administration of fasudil injection and easy degradation of the solution under light.

[0034] (2) Tadalafil and fasudil act on the PDE5 and Rho kinase pathways respectively, and they play a synergistic role when used in combination to treat pulmonary hypertension, and the effect is better than using only one of the drugs alone.

[0035] (3) The preparation process has cheap and easily available excipients, a simple process, and is easy to scale up production. Detailed implementation mode

[0036] The present invention will be further described below in conjunction with specific embodiments.

[0037] Example 1: Preparation of Preparation 1

[0038] 1) Tadalafil total mixing granules

[0039]

[0040]

[0041] (2) Fasudil total mixing granules

[0042]

[0043] Prepare the compound preparation of tadalafil and fasudil according to the formula in the above table, and the preparation method is divided into the following steps:

[0044] (1) Pass the tadalafil raw material drug and lactose through a sieving machine, and then add them to a high-shear wet granulator together with hydroxypropyl cellulose and cross-linked carboxymethyl cellulose sodium for premixing.

[0045] (2) Add sodium lauryl sulfate and hydroxypropyl cellulose to purified water, stir and dissolve to prepare a binder solution with a total concentration of 4%.

[0046] (3) Add the binder solution prepared in step (2) to the mixture in step (1) using a high-shear wet granulator for granulation, while stirring and shearing, with a stirring speed of 240 rpm, a cutting speed of 1000 rpm, and a granulation time of 4.0 min.

[0047] (4) After sieving the granules obtained in step (3), transfer them to a fluidized bed for drying.

[0048] (5) Granulate the dry granules obtained in step (4), and then blend them with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate;

[0049] (6) Pass the fasudil raw material drug and lactose through a sieve using a granulator, and then add them together with polyvinylpyrrolidone and sodium carboxymethyl starch to a high-shear wet granulator for premixing;

[0050] (7) Add purified water to the mixture in step (6) using a high-shear wet granulator to granulate, while stirring and shearing simultaneously. The stirring speed is 240 rpm, the cutting speed is 2000 rpm, and the granulation time is 6.0 min;

[0051] (8) Granulate the granules obtained in step (7), and then transfer them to a fluidized bed for drying;

[0052] (9) Granulate the dry granules obtained in step (8), and then blend them with sodium carboxymethyl starch and talc;

[0053] (10) Place the total mixed granules obtained in step (5) in the first feeding hopper of a tablet press, and place the total mixed granules obtained in step (9) in the second feeding hopper for double-layer pressing.

[0054] Preparation of the formulation 2 in Example 2

[0055] (1) Total mixed granules of tadalafil

[0056]

[0057] (2) Total mixed granules of fasudil

[0058]

[0059] Prepare the compound formulation of tadalafil and fasudil according to the formula in the above table. The preparation method is divided into the following steps:

[0060] (1) Pass the tadalafil raw material drug and lactose through a sieve using a granulator, and then add them together with hydroxypropyl cellulose and croscarmellose sodium to a high-shear wet granulator for premixing;

[0061] (2) Add sodium lauryl sulfate to purified water, stir and dissolve to prepare an adhesive solution with a concentration of 1%;

[0062] (3) Add the adhesive solution prepared in step (2) to the mixture in step (1) using a high-shear wet granulator to granulate, while stirring and shearing simultaneously. The stirring speed is 240 rpm, the cutting speed is 1500 rpm, and the granulation time is 5.0 min;

[0063] (4) Granulate the granules obtained in step (3), and then transfer them to a fluidized bed for drying;

[0064] (5) Granulate the dry granules obtained in step (4), and then blend them with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate;

[0065] (6) Pass the fasudil API and lactose through a sieve of a granulator, and then add them together with povidone and sodium carboxymethyl starch to a high-shear wet granulator for premixing;

[0066] (7) Add povidone to purified water, stir and dissolve it to prepare a binder solution with a concentration of 5%;

[0067] (8) Add the binder solution prepared in step (7) to the mixture in step (6) using a high-shear wet granulator for granulation, while stirring and shearing. The stirring speed is 200 rpm, the cutting speed is 1500 rpm, and the granulation time is 5.0 min;

[0068] (9) Transfer the granules obtained in step (8) to a fluidized bed for drying after granulation;

[0069] (10) Granulate the dry granules obtained in step (9), and then blend them with sodium carboxymethyl starch and talc;

[0070] (11) Mix the total mixed granules obtained in step (5) and the total mixed granules obtained in step (10) according to the prescription ratio, and then press them into single-layer tablets.

[0071] Preparation of the formulation 3 in Example 3

[0072] (1) Total mixed granules of tadalafil

[0073]

[0074] (2) Total mixed granules of fasudil

[0075]

[0076] Prepare the compound preparation of tadalafil and fasudil according to the formula in the above table. The preparation method is divided into the following steps:

[0077] (1) Pass the tadalafil API and lactose through a sieve of a granulator, and then add them together with hydroxypropyl cellulose and croscarmellose sodium to a high-shear wet granulator for premixing;

[0078] (2) Add hydroxypropyl cellulose to purified water, stir and dissolve it to prepare a binder solution with a concentration of 2%;

[0079] (3) Add the binder solution prepared in step (2) to the mixture in step (1) using a high-shear wet granulator to granulate while stirring and shearing. The stirring speed is 300 rpm, the cutting speed is 2000 rpm, and the granulation time is 3.0 min;

[0080] (4) Screen the granules obtained in step (3) and transfer them to a fluidized bed for drying;

[0081] (5) Screen the dry granules obtained in step (4) and blend them with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate;

[0082] (6) Screen the fasudil raw material drug and lactose through a granulator, and then premix them with polyvinylpyrrolidone and sodium carboxymethyl starch in a high-shear wet granulator;

[0083] (7) Add purified water to the mixture in step (6) using a high-shear wet granulator to granulate while stirring and shearing. The stirring speed is 200 rpm, the cutting speed is 1000 rpm, and the granulation time is 6.0 min;

[0084] (8) Screen the granules obtained in step (7) and transfer them to a fluidized bed for drying;

[0085] (9) Screen the dry granules obtained in step (8) and blend them with sodium carboxymethyl starch and talc powder;

[0086] (10) Place the total mixed granules obtained in step (5) in the first feeding hopper of a tablet press, and place the total mixed granules obtained in step (9) in the second feeding hopper for double-layer pressing.

[0087] Preparation of Example 4, Preparation of Formulation 4

[0088] (1) Total mixed granules of tadalafil

[0089]

[0090] (2) Total mixed granules of fasudil

[0091]

[0092] Prepare the compound preparation of tadalafil and fasudil according to the formula in the above table. The preparation method is divided into the following steps:

[0093] (1) Screen the tadalafil raw material drug and lactose through a granulator, and then premix them with hydroxypropyl cellulose and croscarmellose sodium in a high-shear wet granulator;

[0094] (2) Add purified water to the mixture obtained in step (1) using a high-shear wet granulator to granulate while performing stirring and shearing. The stirring speed is 240 rpm, the cutting speed is 1500 rpm, and the granulation time is 6.0 min.

[0095] (3) Screen the granules obtained in step (2) and transfer them to a fluidized bed for drying.

[0096] (4) Screen the dry granules obtained in step (3) and blend them with microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0097] (5) Pass fasudil API and lactose through a sieve of a granulator, and then premix them with povidone and sodium carboxymethyl starch in a high-shear wet granulator.

[0098] (6) Add purified water to the mixture obtained in step (5) using a high-shear wet granulator to granulate while performing stirring and shearing. The stirring speed is 240 rpm, the cutting speed is 1500 rpm, and the granulation time is 6.0 min.

[0099] (7) Screen the granules obtained in step (6) and transfer them to a fluidized bed for drying.

[0100] (8) Screen the dry granules obtained in step (7) and blend them with sodium carboxymethyl starch and talc.

[0101] Place the total mixed granules obtained in step (4) in the first feeding hopper of a tablet press, and place the total mixed granules obtained in step (8) in the second feeding hopper for double-layer pressing.

[0102] Example 5 Stability Study

[0103] Conduct a stability study test on the preparations 1-4 obtained in Examples 1-4, that is, place them in an environment of 40 ± 2 °C and RH 75 ± 5% for 30 days to examine the changes in their related substances. The HPLC test results are shown in Table 1.

[0104] Table 1 Stability Study Data

[0105]

[0106] Impurity 1 is a degradation impurity of tadalafil, and impurity 2 is a degradation impurity of fasudil, both of which are internal control impurities listed in the quality standard. From the above stability data, it can be seen that the related substance indicators of the tadalafil and fasudil compound preparation of the present invention have no significant changes, and the total impurities are all <0.5%, which does not affect the drug effect, and the sample quality is qualified and stable.

[0107] Example 6 Dissolution Study

[0108] Determination of tadalafil dissolution: According to the dissolution and release determination method (the second method in General Chapter 0931, Volume IV of the Chinese Pharmacopoeia 2015 Edition), water + 0.5% SDS 9 1000 ml was used as the dissolution medium, and the rotation speed was 50 revolutions per minute.

[0109] Determination of fasudil dissolution: According to the dissolution and release determination method (the second method in General Chapter 0931, Volume IV of the Chinese Pharmacopoeia 2015 Edition), 900 ml of degassed water was used as the dissolution medium, and the rotation speed was 100 revolutions per minute.

[0110] The results are shown in Table 2.

[0111] Table 2 Dissolution data of active substances in the samples

[0112]

[0113] According to the data in the above table, it can be seen that Formulations 1-4 all have relatively ideal dissolution.

[0114] Pharmacodynamic evaluation of Example 7

[0115] Establishment of a pulmonary hypertension rat model: Monocrotaline (MCT) is a bipyrrole alkaloid. After being transformed by P450 monooxygenase in the liver, it reaches the lungs through the blood circulation system, can selectively damage the pulmonary vascular endothelium, and cause chronic vascular inflammatory lesions, which is closer to the clinical pathogenesis of PAH. The method of inducing with MCT is an ideal way to construct a pulmonary hypertension model. At the beginning of the experiment, rats were injected subcutaneously with MCT 60 mg / kg behind the neck to establish a PAH model.

[0116] For the dose of tadalafil, referring to the human dose of 20 mg (calculated based on a standard body weight of 70 kg, approximately 0.3 mg / kg), according to the principle of equivalent dose conversion, it is equivalent to a dose of 0.4 mg for rats (calculated based on a standard body weight of 200 g, approximately 2 mg / kg); similarly, for the dose of fasudil, referring to the human dose of 80 mg, it is equivalent to a dose of 1.6 mg for rats.

[0117] After injection of MCT to establish the model, the pulmonary hypertension rats were randomly divided into the following groups:

[0118] Model group: Given an equal volume of normal saline by gavage once a day.

[0119] Tadalafil group: Given 0.4 mg of tadalafil by gavage once a day.

[0120] Fasudil group: Given 1.6 mg of fasudil by gavage once a day.

[0121] Tadalafil + Fasudil group: gavaged with 0.4 mg tadalafil + 1.6 mg fasudil once a day.

[0122] One week after MCT injection for modeling, the above groups were gavaged with the corresponding drugs daily. After 3 weeks, catheter manometry was performed on the rats in each group (systemic circulation pressure mSAP, right ventricular pressure mRVP, pulmonary artery pressure mPAP). The results are shown in Table 3.

[0123] Table 3 Changes in blood pressure of experimental rats in each group (mean ± SD, n = 6)

[0124]

[0125] From the data in the above table, it can be seen that the combination of tadalafil and fasudil can play a good synergistic effect, improve the hemodynamic changes caused by pulmonary hypertension, and the combined application of the two drugs is better than the single use.

Claims

1. A pharmaceutical composition, characterized in that, The described composition uses tadalafil and fasudil as active pharmaceutical ingredients, wherein the weight ratio of tadalafil to fasudil as the two active ingredients is 1:25 to 1:2 (w / w).

2. The pharmaceutical composition according to claim 1, wherein The described tadalafil can be the active ingredient itself or its pharmaceutically acceptable salt, and the described fasudil can be its hydrochloride salt or other forms of pharmaceutically acceptable salts.

3. The pharmaceutical composition according to claim 1, wherein The described pharmaceutical composition is a tablet, powder, liquid preparation, capsule, granule, aerosol inhalant or infusion.

4. The pharmaceutical composition according to claim 3, characterized in that, The described pharmaceutical composition is a tablet, and in terms of mass percentage content, it contains 1-5% tadalafil, 10-25% fasudil, and the balance is pharmaceutically acceptable excipients.

5. The pharmaceutical composition according to claim 4, wherein The described pharmaceutical composition is a tablet, and in terms of mass percentage content, its component contents are: 1-5% tadalafil, 10-25% fasudil, 60-75% filler, 1-4% binder, 5-8% disintegrant, 0.5-2.0% lubricant, 0.1-0.5% solubilizer.

6. The pharmaceutical composition according to claim 5, wherein The described filler is selected from one or more of lactose, mannitol, microcrystalline cellulose, calcium hydrogen phosphate, and starch; The described binder is selected from one or more of polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, ethyl cellulose, and sodium carboxymethyl cellulose; The described disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch; The described lubricant is selected from one or more of magnesium stearate, stearic acid, silica, sodium stearyl fumarate, and talc; The described solubilizer is selected from one or more of poloxamer, sodium lauryl sulfate, and Tween, and preferably sodium lauryl sulfate.

7. The pharmaceutical composition according to claim 6, wherein The described filler is lactose or microcrystalline cellulose, the described binder is hydroxypropyl cellulose or hypromellose, the described disintegrant is croscarmellose sodium, the described solubilizer is sodium lauryl sulfate, and the described lubricant is magnesium stearate.

8. The preparation method of the pharmaceutical composition according to any one of claims 5-7, characterized in that, Comprising the following steps: Step S1, premix the tadalafil raw material with the filler, binder, and disintegrant; Step S2, dissolve the solubilizer and binder in purified water to prepare a binder solution, add the binder solution to the premix obtained in Step S1, and granulate using a granulator; Step S3, screen the granules obtained in Step S2 and then dry; Step S4, screen the dry granules obtained in Step S3 and then blend them with the filler, disintegrant, and lubricant; Step S5, premix the fasudil raw material with the filler, binder, and disintegrant; Step S6, dissolve the binder in purified water to prepare a binder solution, add the binder solution to the premix obtained in Step S5, and granulate using a granulator; Step S7, screen the granules prepared in Step S6 and then dry; Step S8, screen the dry granules obtained in Step S7 and then blend them with the disintegrant and lubricant; Step S9: Compress the total mixed granules obtained in Step S4 and Step S8 into bilayer tablets using a bilayer tablet press, or compress the total mixed granules obtained in Step S4 and Step S8 into monolayer tablets after mixing.

9. Use of the pharmaceutical composition according to any one of claims 1-7 in the preparation of a medicament for treating pulmonary hypertension.

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