CN111096968A - SGC-003 pharmaceutical composition, preparation method and application thereof - Google Patents

Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical composition containing a compound shown in formula I or a pharmaceutically acceptable salt thereof. Specifically, the pharmaceutical composition comprises a compound shown as a formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable auxiliary materials, wherein the content of the compound shown as the formula I or the pharmaceutically acceptable salt thereof is 0.01% -1% by weight of the pharmaceutical composition. The invention also relates to a preparation method and application of the pharmaceutical composition. The pharmaceutical composition, in particular to an oral tablet, has the advantages of convenient taking, reduction of the time required by the disintegration in the stomach, high dissolution rate, quick response and the like(ii) a Animal drug test results show that the composition has better bioavailability and pharmacokinetic properties.

Description

SGC-003 pharmaceutical composition, preparation method and application thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical composition containing 4, 6-diamino-2- [1- (3-fluorothiophene-2-yl) methyl-1H-pyrazolo [3, 4-b ] pyridine-3-yl ] -5-pyrimidinyl-N-methyl carbamate (SGC-003 for short). The invention also relates to a preparation method and application of the pharmaceutical composition.

Background

Pulmonary hypertension (PAH) is a chronic disease which is rarely seen clinically, and is mainly caused by abnormal growth, hyperplasia, irreversible reconstruction and contraction of blood vessels, which causes thrombosis, increase of peripheral vascular resistance and increase of Pulmonary artery pressure, so that right ventricular dysfunction occurs, and finally right ventricular exhaustion and death are caused. The clinical symptoms of PAH are atypical and nonspecific. Although the incidence of the disease is low, the misdiagnosis rate is as high as 90 percent, and the common heart disease or asthma can be easily misdiagnosed. Many patients are already in the middle and advanced stage of the disease at the time of definitive diagnosis due to misdiagnosis or unknown diagnosis, which is not favorable for prognosis. The average age of onset of PAH is 36 years, with 75% of patients grouped in the age group of 20-40 years, 15% under 20 years, and women with a higher incidence than men.

Among the drugs commonly used clinically for the treatment of PAH are prostacyclin and its analogs, endothelin receptor antagonists, phosphodiesterase-5 inhibitors (PDE-5) and soluble guanylate cyclase (sGC) agonists. Prostacyclin has a vascular dilating effect and can promote the formation of cyclic Adenosine Monophosphate (AMP) to inhibit vascular smooth muscle cell proliferation and platelet aggregation. Currently, only inhaled iloprost is approved to be on the market in China. Endothelin-1 (endothelin-1, ET-1) secreted by endothelial cells is currently known to be the most potent vasoconstrictor. ET-1 receptors include ETA and ETB, and ET-1 binds to different receptors and exerts different effects on blood vessels. Vasoconstriction is primarily mediated by ETA, and proliferation of vascular smooth muscle cells is co-mediated by ETA and ETB. Endothelin receptor antagonists can block the ET-1 receptor, resulting in vascular dilation and inhibition of pulmonary vascular proliferation. Over-expression of PDE-5 results in inactivation of cGMP through massive hydrolysis of cyclic guanosine monophosphate (cGMP), which results in failure to exert the vasodilatory and cell proliferation inhibitory effects of Nitric Oxide (NO). PDE-5 inhibitors inhibit PDE-5 activity, reducing degradation of cGMP, enabling NO to function, thereby potentiating cGMP-mediated pulmonary vasodilation and antiproliferative capacity of vascular smooth muscle cells. The mechanism of action of sGC agonists is to directly stimulate sGC and enhance its sensitivity to low levels of NO, resulting in increased cGMP production and subsequent vasodilation, thereby lowering blood pressure. Riociguat (brand name: Adempas; Chinese name: Riociguat) developed by Bayer corporation belongs to sGC agonists.

The inventor carries out structural transformation by taking riociguat as a lead compound to obtain a series of compounds, and selects SGC-003 (relative molecular mass of 424.8) as a candidate compound, wherein the structural formula of the compound is 4, 6-diamino-2- [1- (3-fluorothiophene-2-yl) methyl-1H-pyrazolo [3, 4-b ] pyridine-3-yl ] -5-pyrimidyl-N-methyl carbamate (SGC-003 for short) is used as a soluble guanylate cyclase agonist, and the chemical structural formula of the compound is shown as a formula I.

Pharmacodynamic evaluation and research show that the SGC-003 for preventing administration can obviously reduce pulmonary arterial pressure and right ventricular index of rats and improve right ventricular hypertrophy, and has stronger pharmacological action compared with riociguat. The influence of SGC-003 on the surface area of hypertrophic cardiac muscle cells, the total protein content and the mRNA expression of atrial natriuretic peptide genes is detected, and the SGC-003 has more obvious protective effect on the cardiac muscle cells, less adverse reactions, good clinical safety and effectiveness evaluation, higher absolute bioavailability than riociguat and very wide application prospect.

The invention develops the SGC-003 oral preparation according to the characteristics of the medicine and the requirement of clinical medication.

Disclosure of Invention

The inventor prepares a pharmaceutical composition containing SGC-003 through intensive research and creative work. The inventor surprisingly finds that the pharmaceutical composition, particularly the oral tablet, has the advantages of convenient taking, reduction of the time required by the disintegration in the stomach, high dissolution rate, quick response and the like; animal drug test results show that the composition has better bioavailability and pharmacokinetic properties. The following invention is thus provided:

the invention relates to a pharmaceutical composition, which comprises a compound shown in a formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable auxiliary materials.

Wherein the compound of formula I or a pharmaceutically acceptable salt thereof is present in an amount of 0.01% to 1%, preferably 0.05% to 0.5%, more preferably 0.06% to 0.3%, e.g. 0.06%, 1.2% or 3% by weight of the pharmaceutical composition.

In some embodiments of the present invention, the pharmaceutical composition is a solid formulation, preferably a tablet.

In some embodiments of the present invention, the pharmaceutical composition is a pharmaceutical composition for treating and/or preventing pulmonary hypertension; preferably, the pulmonary hypertension is chronic thromboembolic pulmonary hypertension.

In some embodiments of the invention, the pharmaceutical composition is a compound of formula I or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, the pharmaceutical composition wherein the compound of formula I or a pharmaceutically acceptable salt thereof is a first active ingredient, and further comprises a second active ingredient different from the first active ingredient having anti-pulmonary hypertension properties; preferably, the second active ingredient is one or more selected from the group consisting of prostacyclin and analogs thereof (e.g., iloprost), endothelin receptor antagonists (e.g., endothelin-1), phosphodiesterase-5 inhibitors and soluble guanylate cyclase agonists other than a compound of formula I or a pharmaceutically acceptable salt thereof.

In some embodiments of the present invention, the pharmaceutical composition, wherein the excipient is one or more selected from the group consisting of a filler, a disintegrant, a binder, a lubricant, and a coating agent; preferably, it also contains a wetting agent.

In some embodiments of the invention, the pharmaceutical composition is characterized by any one or more of the following items (1) to (6):

(1) the filler is one or more selected from lactose, microcrystalline cellulose, corn starch, dextrin and pregelatinized starch, and is preferably lactose and/or microcrystalline cellulose;

(2) the disintegrant is one or more selected from microcrystalline cellulose, crospovidone (such as crospovidone XL-10), starch, sodium carboxymethyl starch, croscarmellose sodium and silicon dioxide, preferably crospovidone and/or microcrystalline cellulose;

(3) the adhesive is one or more selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, methylcellulose and ethyl cellulose, preferably hydroxypropyl methylcellulose;

(4) the lubricant is one or more selected from magnesium stearate, talcum powder, stearic acid, sodium fumarate, PEG6000, sodium dodecyl sulfate and superfine silica gel powder, and is preferably magnesium stearate;

(5) the coating agent is an Opadry coating premix and/or hydroxypropyl methylcellulose, and preferably the Opadry coating premix;

(6) the wetting agent is selected from water, ethanol and aqueous ethanol solution, preferably water.

In some embodiments of the invention, the pharmaceutical composition, wherein, calculated as the weight percentage of the pharmaceutical composition,

the content of the filler is 70-90%,

the content of the disintegrating agent is 2 to 5 percent,

the content of the adhesive is 2-10%,

the content of the lubricant is 0.1-1%,

the content of the coating agent is 2% -3%;

the content of the wetting agent is 24-25%.

A second aspect of the invention relates to a method of preparing a pharmaceutical composition according to any one of the first aspects of the invention, comprising the steps of:

(1) uniformly mixing the filler and the disintegrant to obtain a first mixture;

(2) adding a binder to the wetting agent to obtain a second mixture;

(3) adding the second mixture into the first mixture, granulating by a wet method, and then finishing and drying to obtain granules;

(4) micronizing the raw material medicine of the compound of the formula I or the pharmaceutically acceptable salt thereof to obtain micro powder;

(5) uniformly spraying the micro powder in the step (4) onto the particles in the step (3), and then drying to obtain dried particles;

(6) adding a lubricant into the dried particles obtained in the step (5), uniformly mixing, and tabletting to obtain bare chips;

(7) coating the bare chips obtained in the step (6) to prepare tablets.

A third aspect of the present invention relates to a use of the pharmaceutical composition according to any one of the first aspect for the preparation of a medicament for the treatment and/or prevention of pulmonary hypertension; preferably, the pulmonary hypertension is chronic thromboembolic pulmonary hypertension.

In the present invention, the terms "first" (e.g., first active ingredient, etc.) or "second" (e.g., second active ingredient, etc.) are used for descriptive purposes only and not for purposes of strict order or sequence unless otherwise specified.

Drawings

FIG. 1: mean drug-time curve (n ═ 5, Mean ± SD) after gavage of male beagle dogs at different doses of SGC-003.

FIG. 2: mean drug-time curve after vein or gavage of SGC-003(0.5mg/kg) in male beagle dogs (n ═ 5, Mean ± SD).

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

According to the clinical medication requirement, the dosage form of the product is determined to be oral tablets, and three specifications of 0.5 mg/tablet, 1.0 mg/tablet and 2.5 mg/tablet are set. The tablets with the three specifications are consistent in weight and size, are distinguished by film coatings with different colors, are white or similar to white after the film coatings are removed, and are controlled by adjusting the prescription amount of lactose. According to the guiding principle of research of chemical pharmaceutical preparations, the composition, production process, packaging material, stability and the like of the prescription of the product are investigated, and the prescription and the preparation process of the product are determined.

Example 1: SGC-003 oral tablet (Specification 0.5mg)

(1) Uniformly mixing 70-90% of filler lactose and microcrystalline cellulose, and 70-102-5% of disintegrant microcrystalline cellulose and crospovidone XL to obtain a first mixture;

(2) adding hydroxypropyl methyl cellulose serving as an adhesive into a pure water solution to prepare a 3% hydroxypropyl methyl cellulose water solution to obtain a second mixture;

(3) adding the second mixture into the first mixture, granulating by a wet method, and then finishing and drying to obtain granules;

(4) carrying out micronization treatment on the SGC-003 bulk drug to obtain micro powder;

(5) uniformly spraying the micro powder in the step (4) onto the particles in the step (3) according to the specification of 5g/1 ten thousand tablets, and then drying to obtain dried particles;

(6) adding 0.1% -1% of lubricant magnesium stearate into the dried granules obtained in the step (5), uniformly mixing, and then tabletting to obtain bare chips;

(7) and (4) adding the bare chips obtained in the step (6) into an Opadry premix for coating, and increasing the weight by 2% -3% to obtain the tablets.

Example 2: SGC-003 oral tablet (Specification 1.0mg)

(1) Uniformly mixing 70-90% of filler lactose and microcrystalline cellulose, and 70-102-5% of disintegrant microcrystalline cellulose and crospovidone XL to obtain a first mixture;

(2) adding hydroxypropyl methyl cellulose serving as an adhesive into a pure water solution to prepare a 3% hydroxypropyl methyl cellulose water solution to obtain a second mixture;

(3) adding the second mixture into the first mixture, granulating by a wet method, and then finishing and drying to obtain granules;

(4) carrying out micronization treatment on the SGC-003 bulk drug to obtain micro powder;

(5) uniformly spraying the micro powder in the step (4) onto the particles in the step (3) according to the specification of 10g/1 ten thousand tablets, and then drying to obtain dried particles;

(6) adding 0.1% -1% of lubricant magnesium stearate into the dried granules obtained in the step (5), uniformly mixing, and then tabletting to obtain bare chips;

(7) and (4) adding the bare chips obtained in the step (6) into an Opadry premix for coating, and increasing the weight by 2% -3% to obtain the tablets.

Example 3: SGC-003 oral tablet (Specification 2.5mg)

(1) Uniformly mixing 70-90% of filler lactose and microcrystalline cellulose, and 70-102-5% of disintegrant microcrystalline cellulose and crospovidone XL to obtain a first mixture;

(2) adding hydroxypropyl methyl cellulose serving as an adhesive into a pure water solution to prepare a 3% hydroxypropyl methyl cellulose water solution to obtain a second mixture;

(3) adding the second mixture into the first mixture, granulating by a wet method, and then finishing and drying to obtain granules;

(4) carrying out micronization treatment on the SGC-003 bulk drug to obtain micro powder;

(5) uniformly spraying the micro powder in the step (4) onto the particles in the step (3) according to the specification of 25g/1 ten thousand tablets, and then drying to obtain dried particles;

(6) adding 0.1% -1% of lubricant magnesium stearate into the dried granules obtained in the step (5), uniformly mixing, and then tabletting to obtain bare chips;

(7) and (4) adding the bare chips obtained in the step (6) into an Opadry premix for coating, and increasing the weight by 2% -3% to obtain the tablets.

The samples prepared in the above preparation examples were used for pharmacokinetic testing, see examples below.

Example 4: comparison of bioavailability of SGC-003 different tablets for beagle dogs

1) Experimental animals:

beagle dogs, body weight 10 + -2 kg. Purchased from beijing marts biotechnology limited, laboratory animal license number: SCXK- (Jing) 2011-. The animal is raised in a first-level animal room in the animal center of the military medical research institute.

2) Experimental reagent:

LL-5, powder, 99% pure; provided by the institute of poisonous drug research of military medical institute.

Acetonitrile, chromatographic purity, product of Fisher Scientific company.

Formic acid, chromatographically pure, product of the company DIKMA.

DMSO, chromatographic grade, Sigma-Aldrich.

SGC-003 PEG solution, prepared as follows:

① PEG-400 is measured accurately and prepared into a solution with PEG-400 content of 5% (v/v) in normal saline for injection.

② the SGC-003 raw material drug is accurately weighed, added into the 5 percent PEG-400 solution for dissolution, and placed in an ultrasonic water bath for 5 minutes to be completely dissolved, wherein the concentration of the SGC-003 drug is 0.25mg/mL or 0.5mg/mL (m/v).

SGC-003 CMC suspension was prepared as follows:

① Sodium carboxymethylcellulose (CMC) is weighed accurately, and prepared into a solution with a CMC content of 2% (m/v) in physiological saline for injection, and the solution is stirred on a stirrer for 4-8 hours to be dissolved completely.

② the SGC-003 bulk drug is accurately weighed, added into the 2 percent CMC solution, fully stirred and placed in an ultrasonic water bath for 5 minutes to ensure that the suspension is uniform, and the concentration of the SGC-003 is 0.25mg/mL (m/v).

3) Sample treatment:

0.050mL of rat plasma or beagle plasma is taken, 0.005mL of blank physiological saline is added and mixed evenly, 0.15mL of internal standard acetonitrile solution (LL-5, 200ng/mL) is added, after sufficient oscillation, centrifugation is carried out at 14000rpm for 10 minutes, 10 mu L of supernatant is taken and injected into LC-MS/MS for analysis and determination.

4) The experimental method comprises the following steps:

the effect of different tablet types and solvent types on the bioavailability of SGC-003 was compared. The experiment has 5 different treatment groups, namely a PEG solution intravenous administration group, a PEG solution oral administration group, a CMC suspension oral administration group, a 200-mesh sieve tablet oral administration group and a micro-powder tablet oral administration group. The 200 mesh sieve tablet and the micronized tablet both contain SGC-0032.5 mg per tablet, one tablet per dog per administration, and the dosage is about 0.25 mg/kg. SGC-003 PEG solution and CMC suspension were prepared at 0.25mg/mL, 10mL per dog per administration.

4 beagle dogs weighing about 10kg were given 5 cycles of self-control cross-dosing with a one week washout period for each dosing period. Animals were fasted for 12 hours before each dose, allowed free access to water, and approximately 10mL of water was added immediately after dosing. The oral administration group alternately takes 2mL of blood from the veins of the extremities before administration and 5, 15, 30, 45min and 1, 2, 4, 6, 8, 12, 24h after administration, and the intravenous administration group alternately takes 2mL of blood from the veins of the extremities before administration and 2, 5, 15, 30, 45min and 1, 2, 4, 6, 8, 12, 24h after administration. Centrifuging the blood sampling sample for 15min at 2000g, and storing the separated blood plasma in a refrigerator at the temperature of 20 ℃ below zero for treatment.

By using

6.3 pharmacokinetic program analyzes the measured data and calculates the main pharmacokinetic parameters.

5) The experimental results are as follows:

plasma concentration values of SGC-003 in beagle dogs at various time points after administration are shown in table 1 below. From WinNonlin software, each major pharmacokinetic parameter was calculated as shown in table 2 below.

Table 1: plasma levels in beagle dogs at various time points after administration of SGC-003 (n ═ 4)

Table 2: major pharmacokinetic parameters after SGC-003 administration in beagle dogs (n ═ 4)

The oral group of 200 mesh sieve tablets was used as a reference group, and the other groups were compared with the reference group, and the group equivalence analysis was performed for three parameters of Cmax, AUClast, and AUCINF _ obs, to obtain the parameters in table 1. As can be seen from the table parameters, both the Cmax and AUC of tablets after SGC-003 micronization were improved (ratio greater than 100%) and significant (ratio failed to fall within the range of 80% -120% at 90% confidence interval) compared to oral 200 mesh tablets. At the same time, higher Cmax or AUC relative to 200 mesh screen was also obtained with oral PEG solution or CMC suspension, and this difference was significant. This suggests that absorption of SGC-003 in beagle dogs may be correlated with its dissolution state, and that exposure of the drug to the body increases when the dissolution state is better. Micronized tablets are more favorable to dissolution of the drug than 200 mesh tablets, and therefore better drug exposure is also obtained.

Example 5: bioavailability study of oral SGC-003 in beagle dogs

1) Experimental methods

Reference rats were dosed with 5 male beagle dogs per group.

The 0.5mg/kg dose group of the above 5 beagle dogs was administered by intravenous injection again at equal doses at least one week after gavage (beyond the washout period), and the absolute bioavailability was calculated.

Beagle dogs were administered intravenously (0.5 mg/kg; n-5) and gavage (0.5 mg/kg; n-5) using a two-cycle crossover, self-control experimental design. The intervals are one week cleaning period. Fasting was performed for 12 hours before administration and water was freely available. 2mL of blood is alternately collected from three non-dosed limb veins respectively before and 2, 5, 15, 30, 45 minutes and 1, 2, 4, 6, 8, 12 and 24 hours after dosing, the blood is centrifuged for 15 minutes at 2000g, and the blood plasma is separated and stored in a refrigerator at the temperature of-20 ℃ for treatment.

2) Results of the experiment

The mean plasma concentrations of beagle dogs after oral and intravenous administration of SGC-003(0.5mg/kg) are shown in Table 3, the plasma concentration-time curves are shown in FIG. 2, and the main pharmacokinetic parameters are shown in Table 4.

Table 3: average plasma concentration in beagle after intravenous and intragastric administration of SGC-003(0.5mg/kg) (n ═ 5)

Table 4: major pharmacokinetic parameters after beagle intravenous and gavage of SGC-003(0.5mg/kg) (n ═ 5)

The results showed that the absolute bioavailability was 78% and 80% calculated by AUC (0-t) and AUC (0- ∞), respectively, showing that oral administration of SGC-003 by beagle dog was better absorbed.

Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (10)

1. A SGC-003 pharmaceutical composition comprises a compound shown as a formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable auxiliary materials,

wherein the compound of formula I or a pharmaceutically acceptable salt thereof is present in an amount of 0.01% to 1%, preferably 0.05% to 0.5%, more preferably 0.06% to 0.3%, e.g. 0.06%, 1.2% or 3% by weight of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, which is a solid formulation, preferably a tablet.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a pharmaceutical composition for the treatment and/or prevention of pulmonary hypertension; preferably the pulmonary hypertension is chronic thromboembolic pulmonary hypertension.

4. The pharmaceutical composition according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is the only active ingredient.

5. The pharmaceutical composition according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is a first active ingredient and the pharmaceutical composition further comprises a second active ingredient different from the first active ingredient having anti-pulmonary hypertension properties; preferably, the second active ingredient is one or more selected from the group consisting of prostacyclin and analogs thereof (e.g., iloprost), endothelin receptor antagonists (e.g., endothelin-1), phosphodiesterase-5 inhibitors and soluble guanylate cyclase agonists other than a compound of formula I or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the excipient is one or more selected from the group consisting of a filler, a disintegrant, a binder, a lubricant, and a coating agent; preferably, it also contains a wetting agent.

7. The pharmaceutical composition according to claim 6, characterized by any one or more of the following (1) to (6):

(1) the filler is one or more selected from lactose, microcrystalline cellulose, corn starch, dextrin and pregelatinized starch, and is preferably lactose and/or microcrystalline cellulose;

(2) the disintegrant is one or more selected from microcrystalline cellulose, crospovidone (such as crospovidone XL-10), starch, sodium carboxymethyl starch, croscarmellose sodium and silicon dioxide, preferably crospovidone and/or microcrystalline cellulose;

(3) the adhesive is one or more selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, methylcellulose and ethyl cellulose, preferably hydroxypropyl methylcellulose;

(4) the lubricant is one or more selected from magnesium stearate, talcum powder, stearic acid, sodium fumarate, PEG6000, sodium dodecyl sulfate and superfine silica gel powder, and preferably magnesium stearate;

(5) the coating agent is an Opadry coating premix and/or hydroxypropyl methylcellulose, and preferably the Opadry coating premix;

(6) the wetting agent is selected from pure water, ethanol and ethanol water solution, preferably pure water.

8. The pharmaceutical composition according to claim 6 or 7, wherein, calculated as a percentage by weight of the pharmaceutical composition,

the content of the filler is 70-90%,

the content of the disintegrating agent is 2 to 5 percent,

the content of the adhesive is 2-10%,

the content of the lubricant is 0.1-1%,

the content of the coating agent is 2% -3%;

the content of the wetting agent is 24-25%.

9. A process for preparing a pharmaceutical composition according to any one of claims 1 to 8, comprising the steps of:

(1) uniformly mixing the filler and the disintegrant to obtain a first mixture;

(2) adding a binder to the wetting agent to obtain a second mixture;

(3) adding the second mixture into the first mixture, granulating by a wet method, and then finishing and drying to obtain granules;

(4) micronizing the raw material medicine of the compound of the formula I or the pharmaceutically acceptable salt thereof to obtain micro powder;

(5) uniformly spraying the micro powder in the step (4) onto the particles in the step (3), and then drying to obtain dried particles;

(6) adding a lubricant into the dried particles obtained in the step (5), uniformly mixing, and tabletting to obtain bare chips;

(7) coating the bare chips obtained in the step (6) to prepare tablets.

10. Use of a pharmaceutical composition according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment and/or prevention of pulmonary hypertension; preferably the pulmonary hypertension is chronic thromboembolic pulmonary hypertension.

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