Suction suspension preparation containing SGC receptor stimulant and application thereof

Abstract

The inhalation suspension preparation containing the SGC receptor stimulant comprises the SGC receptor stimulant with an effective therapeutic dose or pharmaceutically acceptable salt of the SGC receptor stimulant, and pharmaceutically acceptable auxiliary materials of the suspension preparation, the pharmaceutically acceptable auxiliary materials of the suspension preparation comprise at least one of a surfactant, a pH regulator, an osmotic pressure regulator and a metal complexing agent; the inhalation suspension preparation containing the riociguat shows good lung absorption efficiency, is beneficial to reaching the same or better treatment level by reducing the administration dosage, can directly act on a diseased region through an administration route, takes effect more quickly compared with oral administration of the riociguat, and has a good application prospect. Gastrointestinal discomfort and systemic hypotension side effects caused by gastrointestinal tract contact and absorption entering a circulatory system can be avoided, the treatment cycle of an oral dosage form dosage titration administration scheme is shortened, and a better treatment scheme is provided for relieving dyspnea and syncope symptoms of pulmonary hypertension patients treated at home.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an inhalation suspension preparation containing an SGC receptor agonist and its use. Background Art

[0002] Pulmonary hypertension (PH) is a serious lung disease that causes abnormally high pressure in the pulmonary arteries, which increases the workload of the heart. As pulmonary artery pressure increases, the heart has to work harder to pump blood throughout the body, which can lead to right ventricular hypertrophy and failure, and can even lead to death[1].

[0003] The World Health Organization (WHO) defines the diagnostic criteria for PH as follows: mean pulmonary artery pressure (mPAP) ≥ 25 mmHG, pulmonary capillary occlusion pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 3 wood units on right cardiac catheterization. According to the 2015 WHO conference, pulmonary hypertension is divided into five categories and more than 20 types: 1. Group 1 PH (WHO Group 1) - PAH, including idiopathic PAH, familial PAH, drug- or toxic-induced PAH, disease-related PAH, pulmonary veno-occlusive disease, and neonatal PAH; 2. Group 2 PH (WHO Group 2): including PH caused by heart disease involving the left heart system and valvular disease of the left heart system; 3. Group 3 PH (WHO Group 3): including PH-ILD, PH-COPD, neonatal lung disease, and PH caused by alveolar-capillary dysplasia; 4. PH caused by chronic embolic pulmonary disease (CTEPH); 5. PH caused by various unknown factors [2].

[0004] Pulmonary arterial hypertension (PAH) is a serious disease characterized by thickening of the pulmonary artery endothelium, muscularis, and adventitia, obstructing pulmonary arterial blood flow and leading to increased pulmonary vascular resistance. It is characterized by persistently elevated pulmonary artery pressure, leading to right heart failure and even death. Pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) gradually increase, accompanied by irreversible pulmonary vascular remodeling. As the disease progresses, patients may experience severe symptoms such as dyspnea, fatigue, chest pain, and even death from right heart failure. Due to the poor prognosis and high mortality rate of pulmonary arterial hypertension, prompt diagnosis and treatment are essential. Treatment options include medication, interventional therapy, and surgery, and the appropriate treatment plan should be selected based on the patient's specific circumstances. Clinically, PAH treatment drugs primarily act through three receptor-signaling pathways: prostaglandin receptors, endothelin receptors, and nitric oxide (NO). According to the route of administration, oral solid preparations mainly include: ambrisentan Letairis, bosentan Tracleer, macitentan Opsumit, riociguat Adempas, vardenafil Revatio, tadalafil Adcirca, selexipag, treprostinil sustained-release tablets Orenitram; inhalation solutions: treprostinil inhalation solution Tyvaso, treprostinil dry powder inhalation Tyvaso DPI, iloprost inhalation solution Ventavis; injection: treprostinil injection Remodulin.

[0005] Based on the type of treatment for PAH, the above medications can be divided into vasodilators and endothelin receptor antagonists. Vasodilators work by dilating blocked and narrowed blood vessels in the lungs, allowing more blood and oxygen to enter the body. Common side effects include arm and leg pain, leg cramps, nausea, diarrhea, and headaches. Endothelin is a substance that narrows blood vessels. Endothelin receptor antagonists exert their therapeutic effects by reversing the effects of endothelin, a substance that narrows blood vessels. Endothelin receptor antagonists are taken orally. Common side effects include headaches, limb swelling, anemia, and bronchitis. Serious side effects include abnormal hemoglobin levels and liver damage [3-4].

[0006] Riociguat tablets have been approved for clinical use in the treatment of PAH and CTEPH, and have potential therapeutic effects in PH-ILD and PH-COPD, both of which are WHO Group 3 pulmonary hypertension. Riociguat stimulates cGMP production in the body's blood vessels, causing vasodilation and relaxation. By dilating pulmonary blood vessels, it reduces pulmonary artery pressure, reduces the burden on the right heart, and improves cardiac function. Common side effects of oral riociguat therapy include headache, dizziness, indigestion, gastrointestinal discomfort or pain, nausea, diarrhea, vomiting, swelling of the limbs, and hypotension. Serious adverse reactions include urticaria, dyspnea, vomiting of blood, severe dyspnea due to pulmonary effusion, cough with foamy mucus, chest pain, and a rapid or irregular heart rate [5-7].

[0007] The World Health Organization (WHO) has developed a classification system for assessing the functional capacity of patients with pulmonary arterial hypertension (PAH) based on the degree of limitation in their daily activities and the symptoms they experience at rest. The specific classifications are: WHO FC I: No activity limitation, daily activities do not cause excessive dyspnea, fatigue, chest pain, and syncope; WHO FC II: Mild activity limitation, but no symptoms at rest, daily activities can cause dyspnea, fatigue, chest pain, and syncope; WHO FC III: Significant activity limitation, but no symptoms at rest, and symptoms such as dyspnea, fatigue, or chest pain can occur at an intensity lower than that of daily activities; WHO FC IV: Any activity can cause discomfort, and even some symptoms can occur at rest, and signs of right heart failure may occur [8]. Patients with pulmonary arterial hypertension will experience symptoms such as dyspnea after climbing stairs or other light activities in daily life. This is because the pulmonary artery of patients with pulmonary arterial hypertension becomes narrow, making it difficult to transport oxygenated blood to the left ventricle. Dyspnea and shortness of breath are the most common symptoms of patients with pulmonary arterial hypertension. Other symptoms include fatigue, syncope, chest pain, and swelling of the legs and ankles [9]. Clinical symptoms of pulmonary hypertension (CTEPH) due to chronic embolic pulmonary disease include shortness of breath when climbing stairs or doing light exercise, tightness in the chest or abdomen, fatigue, syncope, and in extreme cases, coughing up blood. The cause is that tiny blood clots in the lungs block the pulmonary blood vessels, or gradually form scar tissue that narrows the pulmonary blood vessels, making it impossible to transport oxygen from the blood to the left ventricle. The causes of pulmonary hypertension (CTEPH) due to chronic embolic pulmonary disease and pulmonary arterial hypertension (PAH) are similar, and the clinical symptoms of both diseases are mainly dyspnea, accompanied by syncope caused by insufficient oxygen supply

[10] .

[0008] "Dyspnea and associated syncope" are the main clinical symptoms of patients with pulmonary arterial hypertension (PAH) and chronic embolic pulmonary hypertension (CTEPH). It is of great significance to evaluate the effect of drug treatment on the relief of this symptom. A clinical trial of oral riociguat for the treatment of pulmonary arterial hypertension (PATENT-1) used the Borg CR10 scale to evaluate the effect of oral administration of different doses of riociguat on the improvement of dyspnea symptoms. The results showed that the p value of the oral riociguat 2.5 mg dose group was 0.002, while the p value of the 1.5 mg dose group was not statistically significant

[11] . The results of the clinical trial confirmed the effect of riociguat on relieving the "dyspnea" symptoms of patients with pulmonary arterial hypertension (PAH), but oral administration of 2.5 mg of riociguat is not the preferred dose for clinical treatment. The dose of riociguat should be adjusted according to the individual tolerance of the patient. The starting dose is 0.5 mg, and the dose is increased by 0.5 mg every 2 to 3 weeks to a maximum dose of 2.5 mg. Compared with other lower doses of riociguat, the oral dose of 2.5 mg riociguat has more obvious side effects: the adverse reaction rate of hypotension in patients is higher (when taking this drug, it is necessary to closely monitor changes in patients' vital signs, especially changes in blood pressure, to avoid orthostatic hypotension), and gastrointestinal discomfort reactions such as indigestion, nausea and diarrhea are more obvious.

[0009] Furthermore, according to clinicians' descriptions and patients' subjective experiences, the symptoms of "dyspnea and syncope" are highly unpredictable (patients may find it difficult to anticipate the onset of symptoms during daily activities). In patients with pulmonary arterial hypertension (PAH) and chronic embolic pulmonary disease (CTEPH), the pulmonary blood vessels are blocked or narrowed, preventing the pumping of sufficient oxygen-rich blood to tissues throughout the body. More seriously, the obstruction of oxygen delivery to the brain can lead to transient loss of consciousness and syncope, with a significant number of patients dying during syncope. [12-15] This suggests that improving the accessibility and compliance of pulmonary hypertension medications plays a crucial role in alleviating symptoms and saving lives in patients with pulmonary hypertension.

[0010] Currently, the main clinical treatments for pulmonary arterial hypertension include oral administration, inhalation, and intravenous or subcutaneous injection. Each route has its own unique characteristics [16-17]. Taking riociguat oral tablets as an example, oral riociguat tablets undergo disintegration, dissolution, and absorption in the gastrointestinal tract, with only a small amount of the drug reaching the target organ (lungs). Riociguat has a plasma protein binding rate of 95% in the human body, indicating that less than 5% of the drug circulates as free drug, which is detrimental to its absorption at the lesion site. The pharmacokinetic parameter tmax for oral riociguat tablets is 1.5 hours, further demonstrating that there is a time lag between the absorption of oral drugs into the body and their therapeutic effect at the local lesion site and the onset of symptoms. The tmax of inhaled iloprost solution is 5 minutes (using the BREELIB nebulizer) and 10 minutes (using the I-neb nebulizer), with an overall tmax value of less than 15 minutes. The tmax of inhaled treprostinil solution / dry powder is 0.22±0.25 hours, with an overall tmax of 15 to 30 minutes.[18-19] Treprostinil solution (subcutaneous continuous infusion), ipoprostenol injection, and iloprost injection (currently approved only in some European countries) are currently approved for the treatment of patients with acute and severe pulmonary arterial hypertension and are primarily used in the clinical treatment of acute and severe patients. All three injectable drugs are prostaglandin analogs. Injection can cause significant local pain and requires a steady, continuous rate of systemic infusion (improper operation can cause severe systemic hypotension), making them unsuitable for home use. In contrast, inhaled administration meets the compliance requirements for home use and is relatively simple and safe to use.

[0011] However, there are currently no reports on the inhaled dosage form of riociguat. Summary of the Invention

[0012] Therefore, the technical problem to be solved by the present invention is to provide an inhalation suspension preparation containing an SGC receptor agonist, a preparation method and use thereof.

[0013] To this end, the present invention provides the following technical solutions:

[0014] An inhalation suspension preparation containing an SGC receptor agonist, comprising: an effective therapeutic dose of an SGC receptor agonist or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients for the suspension preparation; the pharmaceutically acceptable excipients for the suspension preparation include at least one of a surfactant, a pH regulator, an osmotic pressure regulator, and a metal chelating agent.

[0015] Furthermore, the SGC receptor agonist includes riociguat.

[0016] Furthermore, the surfactant is selected from at least one of Span, polyoxyethylene lauryl ether, polyoxyethylene stearic acid ether, polysorbates, sorbitol fatty acid esters, polyoxyethylene castor oils, poloxamer, glycerol, polyethylene glycol, oleylamine polyoxyethylene (2) ether, polyoxyethylene 2 stearyl ether, polyoxyethylene (2) stearyl ether, lauryl alcohol polyoxyethylene (4) ether, ethylene oxide and propylene oxide block copolymer, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, monoglyceride, glycerol monolaurate and phospholipid excipients.

[0017] Furthermore, the surfactant is selected from polysorbates and / or sorbitan fatty acid esters, the polysorbates include at least one of Tween 80 and Tween 20, and the sorbitan fatty acid esters include Span 20;

[0018] and / or, in the inhalation suspension preparation, the concentration of Tween 80 is 0.001-0.1 w / v%;

[0019] and / or, in the inhalation suspension preparation, the concentration of Tween 20 is 0.001-0.1 w / v%;

[0020] And / or, in the inhalation suspension preparation, the concentration of Span 20 is 0.0001-0.01 w / v%.

[0021] Furthermore, the pH adjuster includes at least one of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, phosphate buffer, acetate buffer, citrate buffer, acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, malic acid, tartaric acid, phosphoric acid, sodium carbonate, potassium carbonate, sodium hydroxide, sodium sulfate, potassium hydroxide, sodium citrate, and tromethamine.

[0022] Furthermore, the pH adjuster includes at least one of hydrochloric acid, sodium hydroxide, citric acid-sodium citrate buffer, acetic acid-sodium acetate buffer and sodium dihydrogen phosphate-disodium hydrogen phosphate buffer;

[0023] And / or, the pH range of the inhalation suspension formulation is 3.5-9.0.

[0024] Furthermore, in the inhalation suspension preparation, when the pH adjuster is the citric acid-sodium citrate buffer, the citric acid concentration is less than 30 mg / mL and greater than 0 mg / mL, and the sodium citrate concentration is less than 40 mg / mL and greater than 0 mg / mL;

[0025] and / or, in the inhalation suspension preparation, when the pH adjuster is the sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, the concentration of sodium dihydrogen phosphate is less than 20 mg / mL and greater than 0 mg / mL, and the concentration of sodium dihydrogen phosphate is less than 25 mg / mL and greater than 0 mg / mL;

[0026] And / or, in the inhalation suspension preparation, when the pH adjuster is the acetic acid-sodium acetate buffer, the acetic acid concentration is less than 10 mg / mL and greater than 0 mg / mL, and the sodium acetate concentration is less than 15 mg / mL and greater than 0 mg / mL.

[0027] Optionally, the osmotic pressure regulator includes at least one of sodium chloride, potassium chloride, glucose, mannitol, xylitol, lactose, phosphate, citrate, acetate, sodium bromide and magnesium chloride.

[0028] Furthermore, the osmotic pressure regulator is selected from sodium chloride;

[0029] And / or, in the inhalation suspension preparation, the concentration of the osmotic pressure regulator is 0 mg / ml-15 mg / ml, adjusting the osmotic pressure of the inhalation suspension preparation containing the SGC receptor agonist to a range of 200-400 mOsm / kg. Furthermore, the concentration of the osmotic pressure regulator can be any one of 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15 mg / ml, or a range between any two of these values.

[0030] Furthermore, the metal complexing agent includes ethylenediaminetetraacetic acid (EDTA), disodium ethylenediaminetetraacetic acid (EDTA-2Na), tetrasodium ethylenediaminetetraacetic acid (EDTA-4Na) and nitrilotriacetic acid (NTA).

[0031] Furthermore, the metal complexing agent is selected from ethylenediaminetetraacetic acid disodium salt (EDTA-2Na);

[0032] And / or, in the inhalation suspension preparation, the concentration of the metal complexing agent is 0.01 w / v%-1 w / v%, and the w / v ratio is g / L or mg / ml.

[0033] Furthermore, the riociguat or a pharmaceutically acceptable salt thereof is in the form of micronized particles with an average particle size distribution range of 0.1-5 μm;

[0034] And / or, in the inhalation suspension preparation, the concentration of riociguat or a pharmaceutically acceptable salt thereof is 0.05 mg / mL to 10 mg / mL;

[0035] Furthermore, the effective dose of riociguat or a pharmaceutically acceptable salt thereof in the inhalation suspension preparation has a concentration range of 0.25 mg / mL to 2.5 mg / mL.

[0036] And / or, the aerosol particles obtained by atomizing the inhalation suspension preparation have a mass median diameter (MMAD) in the range of 1-10 μm.

[0037] Furthermore, the aerosol particles obtained by atomization of the inhalation suspension preparation have a mass median diameter (MMAD) in the range of 1-5 μm;

[0038] Furthermore, the inhalation suspension preparation is preferably selected from:

[0039] The concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.005 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0040] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0041] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.005 w / v%-0.05 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0042] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.01 w / v%-0.05 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0043] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.005 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0044] Alternatively, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0045] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.005 w / v%-0.05 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0046] Alternatively, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%-0.05 w / v%, citric acid-sodium citrate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%.

[0047] Furthermore, the inhalation suspension preparation is preferably selected from: riociguat or a pharmaceutically acceptable salt thereof at a concentration of less than 5 mg / ml and greater than 0 mg / ml, Tween 20 at 0.05 w / v%, Span 20 at 0.0005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate to adjust the pH to 5-9, NaCl at 0-1.5 mg / ml, and disodium EDTA at 0-0.1 w / v%;

[0048] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, Span 20 is 0.005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0049] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, Span 20 is 0.0005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0050] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%, Span 20 is 0.001 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0051] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, Span 20 is 0.005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0052] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0053] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 7-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0054] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0055] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, Span 20 is 0.0005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0056] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, Span 20 is 0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0057] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, Span 20 is 0.0005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0058] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%, Span 20 is 0.001 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0059] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, Span 20 is 0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0060] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0061] Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%, citric acid-sodium citrate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%;

[0062] Alternatively, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, citric acid-sodium citrate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%.

[0063] The present invention also provides a method for preparing the inhalation suspension preparation containing the SGC receptor agonist, comprising: taking micronized particles of riociguat, adding a solution containing a pharmaceutically acceptable excipient for the suspension preparation, and mixing.

[0064] Furthermore, the D10 of the micronized particles of riociguat is 0.6 to 0.9 μm, the D50 is 1 to 2 μm, and the D90 is 1.5 to 3.5 μm.

[0065] Furthermore, the micronized particles of riociguat are added to a portion of the aqueous solution containing a pharmaceutically acceptable excipient for the suspension formulation, stirred until wetted, and then the remaining aqueous solution containing a pharmaceutically acceptable excipient for the suspension formulation is added and stirred until completely dispersed.

[0066] The inhalation suspension preparation containing the SGC receptor agonist is used in preparing a medicine for treating pulmonary hypertension (PH) disease.

[0067] Furthermore, pulmonary hypertension (PH) diseases are classified according to the WHO, including but not limited to:

[0068] WHO Group 1 pulmonary hypertension (PAH); or

[0069] WHO Group 4 - chronic thromboembolic pulmonary hypertension (CTEPH); or

[0070] WHO Group 3: Pulmonary hypertension caused by respiratory diseases: PH-COPD (Pulmonary hypertension associated with chronic obstructive pulmonary disease) or PH-ILD (Pulmonary hypertension associated with interstitial lung disease).

[0071] Furthermore, the invention also includes the use of the invention in the preparation of a pulmonary administration drug for treating pulmonary hypertension (PH).

[0072] Furthermore, the pulmonary administration medicine includes an inhalation aerosol, an inhalation powder inhalation, an inhalation liquid preparation, a preparation that can be converted into steam, or an inhalation soft mist.

[0073] The technical solution of the present invention has the following advantages:

[0074] 1. The present invention provides an inhalation suspension formulation containing an SGC receptor agonist, comprising: an effective therapeutic dose of an SGC receptor agonist or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients for the suspension formulation; the pharmaceutically acceptable excipients for the suspension formulation include at least one of a surfactant, a pH adjuster, an osmotic pressure regulator, and a metal chelating agent. The present invention has discovered that the development of an inhalation formulation specifically for SGC receptor agonists, such as an inhalation suspension formulation containing riociguat, can be effective via pulmonary administration at a dose lower than that of oral administration. Compared to oral riociguat, pulmonary administration of an inhalation suspension formulation containing riociguat exhibits superior pulmonary absorption efficiency and lung tissue selectivity, facilitating the achievement of equivalent or superior therapeutic levels by reducing the administered dose. Furthermore, pulmonary administration of riociguat can overcome the hypotensive side effect of its vasodilation effect on the circulatory system while reducing the incidence of gastrointestinal discomfort by minimizing direct contact between the drug and the gastrointestinal tract.

[0075] Furthermore, the present invention demonstrates, through animal-level pharmacokinetic and pharmacodynamic studies, that pulmonary administration of a riociguat inhalation suspension formulation can be effective at a dose lower than that of oral administration. Compared to the conventional oral riociguat tablet dosage regimen, which is designed to avoid gastrointestinal discomfort and hypotension side effects: a starting dose of 0.5 mg, with the dose increasing by 0.5 mg every two weeks to the maximum tolerated dose, the riociguat-specific inhalation formulation developed in the present invention avoids the cumbersome dose titration process and shortens the period from initiation of drug administration to clinical benefit for patients.

[0076] 2. The present invention provides an inhalation suspension formulation containing an SGC receptor agonist that can directly target lung lesions via inhalation, achieving a more rapid onset of action compared to oral administration, where the drug is absorbed through the gastrointestinal tract and then diffuses to the lung lesions. This is beneficial for alleviating the symptoms of dyspnea and syncope in patients with pulmonary hypertension. Riociguat inhalation formulations offer excellent compliance and accessibility for homebound patients experiencing episodes of dyspnea or loss of consciousness due to syncope.

[0077] 3. The present invention provides an inhalation suspension formulation containing an SGC receptor agonist, further comprising riociguat or a pharmaceutically acceptable salt thereof at a concentration of less than 5 mg / ml, Tween 20 at 0.005 w / v%-0.05 w / v%, Span 20 at 0.0005 w / v%-0.005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate to adjust the pH to 5-9, NaCl at 0-1.5 w / v%, and disodium EDTA at 0-0.1 w / v%; or, riociguat or a pharmaceutically acceptable salt thereof at a concentration of less than 5 mg / ml, Tween 80 at 0.025 w / v%-0.05 w / v%, Span 20 at 0.0005 w / v%-0.005 w / v%, and phosphorus. The pH value of riociguat or its pharmaceutically acceptable salt is adjusted to 5-9 by sodium dihydrogen phosphate-disodium hydrogen phosphate, NaCl is 0-1.5w / v%, and EDTA disodium is 0-0.1w / v%; or, the concentration of riociguat or its pharmaceutically acceptable salt is less than 5 mg / ml, Tween 20 is 0.005w / v%-0.05w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to 5-9, NaCl is 0-1.5w / v%, and EDTA disodium is 0-0.1w / v%; or, the concentration of riociguat or its pharmaceutically acceptable salt is less than 5 mg / ml, Tween 80 is 0.01w / v%-0.05w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5w / v%, and EDTA disodium is 0-0.1w / v%; Sodium is 0-0.1 w / v%; or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml, Tween 20 is 0.005 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 w / v%, and disodium EDTA is 0-0.1 w / v%; or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml, Tween 80 is 0.025 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1. 5w / v%, EDTA disodium 0-0.1w / v%; or, riociguat or a pharmaceutically acceptable salt thereof has a concentration of less than 5 mg / ml, Tween 20 is 0.005w / v%-0.05w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5w / v%, EDTA disodium 0-0.1w / v%; or, riociguat or a pharmaceutically acceptable salt thereof has a concentration of less than 5 mg / ml, Tween 80 is 0.025w / v%-0.05w / v%, citric acid-sodium citrate is adjusted to pH 5-9, NaCl is 0-1.5w / v%, and EDTA disodium 0-0.1w / v%; the above-mentioned inhalation suspension preparation has better stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0079] Figure 1 is a microscopic image of the agglomeration phenomenon of particles 6, 30, 88, 100, and 106 of the preparation samples in Example 3 of the present invention;

[0080] Figure 2 These are long-term stability microscope images (6 months) of samples 15, 23, 25, 26, 27, 63, 82, and 87 of the formulation in Example 3 of the present invention;

[0081] Figure 3 These are microscope images (6 months) of the long-term stability of formulation samples 107, 110, and 112 in Example 3 of the present invention;

[0082] Figure 4 These are the pharmacokinetic experimental results of pulmonary administration of the inhalation suspension formulation containing riociguat and oral administration of the original reference formulation in Example 5 of the present invention;

[0083] Figure 5 is the result of B-ultrasound-right heart function test in Example 6 of the present invention;

[0084] Figure 6 is the hemodynamic test result in Example 6 of the present invention;

[0085] Figure 7 These are the pathological staining images of the heart in Example 6 of the present invention (the scale bar in the first row is 0-5 mm, and the scale bar in the second row is 0-250 μm);

[0086] Figure 8 : These are lung pathological staining images in Example 6 of the present invention (the scale bar in the first row is 0-500 μm, and the scale bar in the second row is 0-100 μm);

[0087] Figure 9 This is the analysis result of the pulmonary arteriolar media thickness in Example 6 of the present invention. DETAILED DESCRIPTION

[0088] The following examples are provided for a better understanding of the present invention and are not intended to limit the best mode of implementation. They do not limit the content and scope of protection of the present invention. Any product identical or similar to the present invention obtained by anyone under the guidance of the present invention or by combining the features of the present invention with other prior arts shall fall within the scope of protection of the present invention.

[0089] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in this field can be used. If the manufacturer of the reagents or instruments is not specified, they are all commercially available conventional reagents.

[0090] After oral administration, drugs are dissolved in the stomach and absorbed by the gastrointestinal tract. After first-pass metabolism in the liver and intestine, they enter the circulatory system and a portion of the drugs are perfused into various tissues and organs through the circulatory system. Although the bioavailability of riociguat is 94%, the riociguat that takes effect in the lung tissue through the systemic circulation only accounts for a very small portion of the total oral drug

[20] . Compared with oral administration, inhalation administration allows a smaller oral dose of drugs to act directly on the lung tissue to take effect. The reduction of drug content outside the circulatory system and lung tissue can avoid the side effect of hypotension caused by drug vasodilation

[21] . In addition, inhalation administration can reduce the direct contact of drugs with the gastrointestinal tract, and to the greatest extent avoid the gastrointestinal adverse reactions of indigestion and nausea and diarrhea caused by oral drugs. The applicant used two doses and dosage forms of riociguat, oral (10 mg / kg / day) and pulmonary administration (4 mg / kg / day), to conduct drug efficacy experiments on rats with pulmonary hypertension pathological model induced by monocrotaline. The two groups were found to have essentially identical efficacy in improving lung function-related pathological indicators, including right ventricular systolic pressure (RVSP), pulmonary artery pressure (PAP), left ventricular hypertrophy index (RV / (LV+S)), and pulmonary arteriolar media thickness (p<0.001 for the pulmonary administration group and p<0.01 for the oral administration group). Furthermore, microscopic observation of pathological sections of right ventricular and lung tissue revealed that tissue repair was essentially identical under pulmonary administration (4 mg / kg / day) and oral administration (10 mg / kg / day). In summary, compared to oral administration, the dosage for the same efficacy was reduced by 60%. This preliminary indication suggests that riociguat possesses superior lung tissue selectivity, facilitating the achievement of equivalent or superior therapeutic levels through reduced dosage. Based on this, the applicant developed a proprietary inhalation formulation of riociguat (including an inhalation suspension formulation of riociguat). The applicant screened for the optimal pulmonary dose of riociguat to maximize improvements in patients' pulmonary hemodynamic parameters (right ventricular systolic pressure (RVSP), pulmonary artery pressure (PAP), cardiac output (CO), etc.). Furthermore, leveraging the drug's selectivity for lesions, the applicant overcame the hypotensive side effect of its vasodilation effect on the circulatory system, while also minimizing direct contact between the drug and the gastrointestinal tract, thereby reducing the incidence of gastrointestinal discomfort.

[0091] The chemical structural formula of riociguat of the present invention is as follows:

[0092]

[0093] In the present invention, the pharmacokinetic parameters and clinical application scenario characteristics of drugs administered orally, inhaled, and injected in the clinical treatment of pulmonary arterial hypertension were compared. Furthermore, the higher pulmonary absorption efficiency demonstrated by the physicochemical parameters of riociguat and the drug metabolism parameters of pulmonary administration was further combined. It was found that administration of riociguat by inhalation can improve the compliance of clinically critically ill patients with home treatment (avoiding the pain caused by the injection of prostaglandin analogs), quickly relieve the symptoms of "dyspnea and syncope", and thus reduce the mortality rate of pulmonary arterial hypertension.

[0094] In addition, riociguat can also be expanded to the indications of PH-ILD and PH-COPD, the third major category of pulmonary hypertension diseases [22-23]. There is currently no recommended or approved specific drug for the treatment of PH-COPD, and only inhaled treprostinil is currently approved for the treatment of PH-ILD

[24] . There are huge unmet clinical needs for these two major indications, PH-COPD and PH-ILD. From the clinical trial case of oral riociguat for the treatment of PH-ILD (a total of 147 patients were recruited and terminated early due to safety issues in a few patients), we can find the existing problems: a large proportion of PH-ILD patients can benefit from vasodilator treatment, which can largely meet the treatment needs of patients with high mPAP or low cardiac index [25-27]. The drug delivery method used in the clinical trial (oral tablet) may not be ideal, which may also be one of the reasons for the poor treatment effect. Changing the oral tablet treatment method to inhaled pulmonary vasodilator treatment can directly deliver the drug to the lungs, reduce systemic side effects, and reduce the risk of worsening ventilation / perfusion mismatch

[28] .

[0095] BAY 63-2521 (riociguat) is currently the only SGC receptor agonist marketed for the treatment of pulmonary arterial hypertension (PAH). References have been published on studies using BAY 63-2521 (riociguat) to treat rats with pulmonary hypertension induced by subcutaneous injection of monocrotaline. The results showed that oral administration of riociguat (10 mg·kg-1·day-1) for 14 days could partially reverse right ventricular hypertrophy and pulmonary vascular remodeling

[29] .

[0096] BAY 41-8543 is a SGC receptor agonist drug

[30] , which is similar to riociguat in molecular structure, but has not been marketed due to its low bioavailability in humans. Bayer used BAY 41-8543 as a research object to compare the efficacy of its oral dose (10 mg·kg-1·day-1) with that of direct pulmonary administration (3 mg·kg-1·day-1). After 14 days of pulmonary administration of BAY41-8543 (3 mg·kg-1·day-1), the drug achieved the same efficacy as the oral dose of 10 mg·kg-1·day-1 in terms of 1. B-ultrasound detection indicators; 2. hemodynamic parameters; and 3. pathological evaluation of pulmonary vascular remodeling.

[0097] In addition to the fact that a smaller dose of BAY41-8543 can achieve the same therapeutic effect as oral administration, the study of BAY 41-8543 pulmonary administration also focused on the fact that pulmonary administration can avoid the side effect of decreased systemic vascular pressure (SAP) caused by oral treatment. Mosliciguat (BAY 1237592) is Bayer's latest SGC receptor agonist drug developed as an inhaled dry powder formulation. Preclinical study results showed that pulmonary administration can reduce pulmonary aorta pressure and avoid reducing systemic arterial pressure, which was not reflected in the injection of mosliciguat. The above preclinical research cases all illustrate the selective advantage of pulmonary administration for local lesions and its potential to overcome the side effect of hypotension after administration

[31] .

[0098] Example 1 Preparation of Micronized Riociguat Particles

[0099] Riociguat API was micronized using a Noozle Micron JETMILL Pilot ultrafine mill to control the particle size within the desired range. The experimental conditions and results are shown in the table below:

[0100] Table 2. Airflow milling experimental conditions and particle size results

[0101]

[0102] Note: D10, D50, and D90 represent particle size. D10 means that 10% of the particles in the sample are smaller than or equal to this value; D50 means that 50% of the particles in the sample are smaller than or equal to this value; and D90 means that 90% of the particles in the sample are smaller than or equal to this value.

[0103] According to the particle size distribution results after airflow milling, it can be seen that the particle size distribution of riociguat particles after airflow milling is narrow, which meets the requirements for suspension preparation.

[0104] In the treatment of pulmonary hypertension, smooth muscle cells within the pulmonary arteries and arterioles are the therapeutic targets of vasodilators. Inhaled riociguat formulations need to provide localized drug deposition within the lungs, effectively targeting the drug to the pulmonary arteries.

[0105] By controlling the particle size of the micronized API, the aerosolized suspension droplets have an appropriate aerodynamic size distribution. This allows for localized targeting of drug particles to the small respiratory tract, bronchi, and bronchioles, while minimizing deposition in the upper respiratory tract, large airways, and alveoli. Inhalation suspension formulations of the Leoxigua API with the different particle size distributions listed in Table 2 were prepared.

[0106] Example 2 Inhalation suspension formulation containing riociguat

[0107] This example provides 112 formulations for inhalation suspensions containing riociguat. The concentration of riociguat in each of these inhalation suspensions is 2.5 mg / ml. The concentrations of the remaining components are shown in the table below. The raw material for riociguat is the micronized riociguat particles prepared in Example 1 (selection number 5). A 2.5 mg / ml riociguat suspension is prepared by adding 4 ml of dispersant to 50 mg of the micronized riociguat particles. The mixture is stirred magnetically until completely wetted. Then, 16 ml of dispersant is added and stirring is continued until completely dispersed. The dispersant in each formulation is an aqueous solution containing the components in the table below. In the citric acid-sodium citrate buffer pair mentioned in the table below, the citric acid concentration is less than 30 mg / mL and greater than 0 mg / mL, and the sodium citrate concentration is less than 40 mg / mL and greater than 0 mg / mL; in the sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair, the sodium dihydrogen phosphate concentration is less than 20 mg / mL and greater than 0 mg / mL, and the sodium hydrogen phosphate concentration is less than 25 mg / mL and greater than 0 mg / mL; in the acetic acid-sodium acetate buffer pair, the acetic acid concentration is less than 10 mg / mL and greater than 0 mg / mL, and the sodium acetate concentration is less than 15 mg / mL and greater than 0 mg / mL. The osmotic pressures of the 112 formulations of the obtained inhalation suspension preparations ranged from 200 to 400 mOsm / kg.

[0108] Table 3. Prescription of inhalation suspension containing riociguat

[0109]

[0110] Table 4. Prescription of inhalation suspension containing riociguat

[0111]

[0112]

[0113] Table 5. Prescription of inhalation suspension containing riociguat

[0114]

[0115] Table 6. Prescription of inhalation suspension containing riociguat

[0116]

[0117]

[0118] Table 7. Prescription of inhalation suspension containing riociguat

[0119]

[0120] Table 8. Prescription of inhalation suspension containing riociguat

[0121]

[0122]

[0123] Table 9. Prescription of inhalation suspension containing riociguat

[0124]

[0125] Table 10. Prescription of inhalation suspension containing riociguat

[0126]

[0127] Example 3 Stability Study

[0128] 1. Long-term stability of particle size

[0129] In this example, 112 riociguat-containing inhalation suspension formulations prepared in Example 2 were subjected to a long-term stability study. The stability was assessed at 0 days, 14 days, 28 days, 2 months, 6 months, and 12 months under conditions of 25°C / 60% RH. The suspensions were observed for dispersibility, particle distribution, flocculation, aggregation, and redispersibility under optical microscope. The average particle size of the particles in the suspensions was also measured using a dynamic light scattering nanoparticle size analyzer (Malvern Zetasizer Pro). The stability results are shown in the table below. "Difficult to wet" in the table indicates that the formulation was difficult to wet with magnetic stirring after adding 4 ml of dispersant; "Normal" indicates that the formulation was completely wetted with magnetic stirring after adding 4 ml of dispersant.

[0130] Table 11. Long-term stability test of Riociguat suspension products

[0131]

[0132]

[0133]

[0134]

[0135]

[0136] 2. Particle morphology stability (microscope image)

[0137] Six months after the preparation of the riociguat-containing inhalation suspension preparation samples No. 6, 30, 88, 100, and 106 prepared in Example 2, the drug particle morphology was observed under a microscope. Figure 1 As shown, it shows that the particles of samples 6, 30, 88, 100, and 106 showed agglomeration at 6 months.

[0138] Microscopic images of the long-term stability (6 months) of the riociguat-containing inhalation suspension preparation samples 15, 23, 25, 26, 27, 63, 82, 87, 107, 110, and 112 (described in 1 above) are shown in Table 1. Figure 2-Figure 3 As shown in the figure, it shows that the particles of preparation samples 15, 23, 25, 26, 27, 63, 82, 87, 107, 110, and 112 did not show agglomeration phenomenon after 6 months, proving that the riociguat suspension samples prepared under the formulation ratio conditions meet the long-term stability requirements.

[0139] 3. Stability test at 25℃ / 60%RH

[0140] The formulation samples obtained from the 1. Long-term Particle Size Stability Study described above at 0 days (0 months), 6 months, and 12 months were assayed for related substances using a standard HPLC assay for related substances of riociguat, and purity was calculated. Samples exhibiting instability such as agglomeration and caking were not tested further and were designated as N / A.

[0141] Table 12. Riociguat drug purity test results

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] Example 4: Detection of Fine Particle Dose Ratio of Riociguat-Containing Inhalation Suspension Formulation

[0148] Determination method: Pharmacopoeia of the People's Republic of China (2020 edition, Part IV, 0951 Determination of aerodynamic characteristics of fine particles of inhalation preparations), determination method for inhalation liquid preparations (according to 3. Liquid preparations for nebulizers).

[0149] Measuring device: ACI (Andersen Cascade Impactor).

[0150] Sample testing: Fine Particle Fraction (FPF) testing was performed on samples No. 1 to No. 112 prepared in Example 2 that did not exhibit instability such as agglomeration. Twelve months later, the samples whose suspension systems remained stable were retested. The results are shown in Table 13 below.

[0151] Table 13. FPF (Fine Particle Dose Fraction) Test Results of Riociguat Suspension Preparation

[0152]

[0153]

[0154]

[0155] Example 5 Experiment on the lung deposition rate of an inhalation suspension formulation containing riociguat

[0156] Using a microsprayer (rat and mouse intrapulmonary administration nebulizer), 100 μL of a 10 mg / mL riociguat suspension (prepared as a dispersant corresponding to Formula 30 in Example 2) and 200 μL of a 5 mg / mL suspension (prepared as a dispersant corresponding to Formula 30 in Example 2) were drawn and sprayed into the lungs of SD rats (weighing 250 ± 10 g) (3 rats corresponding to each riociguat concentration suspension). After 15 minutes, the rats were anesthetized and dissected from the trachea to the lung tissue. A large amount of drug particles were also deposited in the trachea. However, there was no material exchange between the trachea and the lesion site - the pulmonary artery. Therefore, the tracheal part was cut off and the lung tissue below the trachea was collected. The tissue weight was accurately weighed and the lung tissue (3 lung tissues in each group were put together) was mixed with the homogenate solution at a ratio of weight (mg): volume (μL) = 1:10 and homogenized using a high-throughput grinder. The homogenate solution composition was: 17% H₃PO₄, 2% ascorbic acid, and 50% acetonitrile (ACN containing 0.1% formic acid). The drug content in the supernatant was analyzed using LC-MS, and the result was divided by 3. A 100 μL sample of the 10 mg / mL riociguat suspension was designated Lung_100 μL; a 200 μL sample of the 5 mg / mL riociguat suspension was designated Lung_200 μL. A blank control (Lung_Blank) was also prepared, consisting of a suspension without riociguat, corresponding to the dispersant of Formula 30 in Example 2.

[0157] Table 14. Lung tissue distribution experiment of Riociguat after inhalation (n=3)

[0158]

[0159] Based on the above results, the lung deposition rate for the 10 mg / ml (100 μl) group administered with a microsprayer device was 42.5%, and the lung deposition rate for the 5 mg / ml (200 μl) group was 34.4%. In summary, approximately 40% of the drug was deposited in the lungs via inhalation. Deposition rate = lung tissue riociguat content / total riociguat content in the administered dose × 100%.

[0160] Example 6 Pharmacokinetics of pulmonary administration of an inhalation suspension formulation containing riociguat

[0161] Fifteen male SD rats (250 ± 10 g) were enrolled in this study, with three rats per group receiving the drug. The rats were divided into five groups, each receiving pulmonary doses of 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg, and an oral dose of 10 mg / kg for the reference formulation (2.5 mg riociguat (oral tablets) manufactured by Bayer). The specific experimental groupings and dosing schedule are shown in Table 15 below. Blood was collected from the jugular vein into EDTA-K2 anticoagulant tubes at eight time points: 0.1 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 7 h, and 24 h after administration. Blood was collected from the jugular vein and placed in EDTA-K2 anticoagulant tubes. The blood was centrifuged at 10,000 rpm for 5 min and stored at -80°C. A total of 70 μL of plasma was collected at each time point for riociguat plasma concentration determination. The riociguat suspensions in Groups 1-3 in the table below are the riociguat suspensions prepared according to Prescription 30 in Example 2. Group 4 is the riociguat suspension prepared according to Prescription 30 in Example 2, except that the riociguat concentration in the prepared riociguat suspension is adjusted to 5 mg / mL.

[0162] Table 15 Experimental grouping and experimental drug administration

[0163]

[0164] From the pharmacokinetic parameters of pulmonary administration and oral administration, it can be seen that the parameters of pulmonary administration are: C max , t 1 / 2 Parameters such as t max Compared with the oral original drug group, the C max The values ​​were basically consistent, indicating that riociguat suspension had good absorption efficiency after pulmonary administration.

[0165] Example 7 Pharmacodynamic Evaluation Experiment of Inhalation Suspension Formulation Containing Riociguat

[0166] In this example, the pharmacodynamics of an inhalation suspension formulation containing riociguat was investigated using a pulmonary arterial hypertension (PAH) model.

[0167] (1) Modeling method

[0168] Modeling agent: Monocrotaline MCT, dose: 60 mg / kg, concentration: 30 mg / mL, volume: 2.0 mL / kg

[0169] Modeling process: single subcutaneous injection of MCT.

[0170] (2) Experimental grouping and experimental administration

[0171] A total of 16 SD rats (male, weighing 250±10g) were used in this experiment (the mortality rate was about 5% around day 25 during the model establishment process, and the experimental period was 21 days). The day of model establishment was designated as Day 1. The animals were weighed and randomly divided into groups one day before drug administration, namely the G1 model group (n=4+2), the G2 drug administration group (n=4+2), and the G3 positive drug group (n=4). Specific experimental groups and drug administration are shown in the table below:

[0172] Table 16. Experimental Grouping and Dosing

[0173]

[0174] In the table above, blank solution: 100 μL of 0.005% (w / w) Tween 80 / pH 6 phosphate buffer (without riociguat); Riociguat: The riociguat used in Group 2 consisted of riociguat micropowder dispersed in the dispersant corresponding to Formula 30 in Example 2; Positive drug: 2.5 mg riociguat original drug (oral tablet) manufactured by Bayer. Dosing began on the eighth day after modeling and was administered once daily for a total of 14 days. Groups G1 and G2 were administered by intratracheal instillation, while Group G3 was administered by oral gavage.

[0175] (3) Detection indicators

[0176] 1) B-ultrasound-right heart function test

[0177] Methods: Ultrasound. Animals were anesthetized with 2.5% isoflurane and then maintained with 1.0-1.5% isoflurane. The animals were placed flat on a heating pad. The rats' chests were skinned to reduce ultrasound attenuation. Ultrasound gel was applied to the chest wall. Right ventricular free wall thickness (RVWT) was measured from a modified parasternal long-axis view. The pulmonary valve was selected to measure the RV outflow tract (RVOT) diameter. Tricuspid annular plane systolic excursion (TAPSE) was measured from the junction of the tricuspid plane and the right ventricular free wall using the apical four-chamber view. Pulmonary artery acceleration time (PAAT) was measured as a pulsed-wave Doppler blood flow velocity profile of the right ventricular outflow tract from the parasternal short-axis view.

[0178] Detection indicators include: pulmonary artery acceleration time (PAAT), tricuspid annular plane systolic excursion (TAPSE), cardiac index (CI) (CI = cardiac output CO / BW (CO = stroke volume SV * heart rate HR), right ventricular internal diameter (RVID), and right ventricular freewall thickness (RVWT).

[0179] 2) Hemodynamic testing

[0180] Detection method: After the animal to be tested is anesthetized with 2.5% isoflurane, the right jugular vein is stripped and a catheter equipped with a pressure sensor is inserted into the right ventricle and common carotid artery of the heart for measurement. After the right ventricular index test is completed, a catheter equipped with a pressure sensor is inserted into the pulmonary artery to detect the common carotid artery blood pressure and pulmonary aorta pressure.

[0181] Detection indicators: interventional measurement of animals' right ventricular systolic pressure (RVSP), right ventricular function dp / dt (max), dp / dt (min), common carotid artery blood pressure, and pulmonary artery pressure.

[0182] 3) Lung / right heart pathology analysis.

[0183] 4) Analysis of pulmonary arteriolar media thickness.

[0184] (4) Test results

[0185] The applicant conducted a pharmacodynamic study on the treatment of monocrotaline-induced pulmonary hypertension in rats by orally administering 10 mg / kg / day of riociguat (Group G3) versus 4 mg / kg / day of pulmonary administration (the actual pulmonary administration dose was 1.6 mg / kg / day after converting the actual pulmonary deposition rate) (Group G2). The results showed that:

[0186] B-ultrasound-right heart function test results Figure 5 As shown in the figure, it can be seen that after 14 days of oral / pulmonary administration of monocrotaline-induced pathological rats, B-ultrasound was performed to detect right heart function. Figure 4 The changes in the quantifiable pathological indicators of this test show that the trends of these pathological indicators are consistent after pulmonary and oral administration interventions.

[0187] Hemodynamic test results such as Figure 6 As shown, it can be seen that the mean pulmonary artery pressure (mPAP) of the oral (10 mg / kg / day) dosage group (G3) changed from 30.06 mmHg in the pathological model group (G1) to 31.37 mmHg, while that of the pulmonary administration group (4 mg / kg / day) (G2) decreased to 26.5 mmHg; the average right ventricular systolic pressure (RVSP) of the oral (10 mg / kg / day) treatment group decreased from 28.47 mmHg in the pathological model group to 18.65 mmHg, while that of the pulmonary administration group (4 mg / kg / day) decreased to 21.38 mmHg.

[0188] Heart pathology staining pictures Figure 7 As shown, it can be seen that the right ventricular cardiomyocytes of rats in the pathological model group were hypertrophic and disorderly arranged, while the right ventricular cardiomyocytes of the rats in the pulmonary administration group / oral administration group were relatively neatly arranged, relatively uniform in size, and relatively evenly distributed.

[0189] Lung pathological staining pictures Figure 8 As shown, HE staining results indicate that the lumen of the pulmonary arterioles in the rats in the pathological model group was significantly narrowed, and the smooth muscle was significantly proliferated and hypertrophied. The pathological lesions of the pulmonary arterioles were alleviated after pulmonary and oral administration.

[0190] The results of pulmonary arteriolar media thickness analysis are as follows Figure 9 As shown, the average medial thickness of the pulmonary arterioles in the pathological model group was 18.52 μm, which decreased to 11.21 μm in the oral (10 mg / kg / day) treatment group (p < 0.01), and decreased to 9.44 μm in the pulmonary administration group (4 mg / kg / day) (p < 0.001).

[0191] Based on the improvements in these quantifiable pathological indicators, pulmonary administration of riociguat can be effective at a lower dose than oral administration. The applicants have preliminarily demonstrated through animal efficacy studies that the pulmonary administration of the inhalation suspension formulation containing riociguat of the present invention can be effective at a lower dose than oral administration.

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[0224] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. An inhalation suspension preparation containing an SGC receptor agonist, characterized in that: include: An effective therapeutic dose of an SGC receptor agonist or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for a suspension preparation; the pharmaceutically acceptable excipient for the suspension preparation includes at least one of a surfactant, a pH regulator, an osmotic pressure regulator, and a metal complexing agent.

2. The inhalation suspension preparation containing an SGC receptor agonist according to claim 1, characterized in that The SGC receptor agonists include riociguat.

3. The inhalation suspension preparation containing an SGC receptor agonist according to claim 2, characterized in that The surfactant includes at least one of Span, polyoxyethylene lauryl ether, polyoxyethylene stearic acid ether, polysorbates, sorbitol fatty acid esters, polyoxyethylene castor oils, poloxamer, glycerol, polyethylene glycol, oleylamine polyoxyethylene (2) ether, polyoxyethylene 2 stearyl ether, polyoxyethylene (2) stearyl ether, lauryl alcohol polyoxyethylene (4) ether, ethylene oxide and propylene oxide block copolymer, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, monoglyceride, glycerol monolaurate and phospholipid excipients.

4. The inhalation suspension preparation containing an SGC receptor agonist according to claim 3, characterized in that The surfactant includes polysorbates and / or sorbitan fatty acid esters, the polysorbates include at least one of Tween 80 and Tween 20, and the sorbitan fatty acid esters include Span 20; and / or, in the inhalation suspension preparation, the concentration of Tween 80 is 0.001-0.1 w / v%; and / or, in the inhalation suspension preparation, the concentration of Tween 20 is 0.001-0.1 w / v%; And / or, in the inhalation suspension preparation, the concentration of Span 20 is 0.0001-0.01 w / v%.

5. The inhalation suspension preparation containing an SGC receptor agonist according to any one of claims 1 to 4, characterized in that: The pH adjuster includes at least one of sodium dihydrogen phosphate, disodium hydrogen phosphate, citric acid, phosphate buffer, acetate buffer, citrate buffer, acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, malic acid, tartaric acid, phosphoric acid, sodium carbonate, potassium carbonate, sodium hydroxide, sodium sulfate, potassium hydroxide, sodium citrate, and tromethamine.

6. The inhalation suspension preparation containing an SGC receptor agonist according to claim 5, characterized in that The pH regulator comprises at least one of hydrochloric acid, sodium hydroxide, citric acid-sodium citrate buffer, acetic acid-sodium acetate buffer and sodium dihydrogen phosphate-disodium hydrogen phosphate buffer; And / or, the pH range of the inhalation suspension formulation is 3.5-9.

0.

7. The inhalation suspension preparation containing an SGC receptor agonist according to claim 5 or 6, characterized in that: In the inhalation suspension preparation, when the pH adjuster is a citric acid-sodium citrate buffer, the citric acid concentration is less than 30 mg / mL and greater than 0 mg / mL, and the sodium citrate concentration is less than 40 mg / mL and greater than 0 mg / mL; and / or, in the inhalation suspension preparation, when the pH adjuster is sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, the concentration of sodium dihydrogen phosphate is less than 20 mg / mL and greater than 0 mg / mL, and the concentration of sodium dihydrogen phosphate is less than 25 mg / mL and greater than 0 mg / mL; And / or, in the inhalation suspension preparation, when the pH adjuster is acetic acid-sodium acetate buffer, the acetic acid concentration is less than 10 mg / mL and greater than 0 mg / mL, and the sodium acetate concentration is less than 15 mg / mL and greater than 0 mg / mL.

8. The inhalation suspension preparation containing an SGC receptor agonist according to any one of claims 1 to 7, characterized in that: The osmotic pressure regulator includes at least one of sodium chloride, potassium chloride, glucose, mannitol, xylitol, lactose, phosphate, citrate, acetate, sodium bromide and magnesium chloride.

9. The inhalation suspension preparation containing an SGC receptor agonist according to claim 8, characterized in that The osmotic pressure regulator is selected from sodium chloride; And / or, in the inhalation suspension preparation, the concentration of the osmotic pressure regulator is 0 mg / ml-15 mg / ml, and the osmotic pressure range of the inhalation suspension preparation containing the SGC receptor agonist is adjusted to 200-400 mOsm / kg.

10. The inhalation suspension preparation containing an SGC receptor agonist according to any one of claims 1 to 9, characterized in that: The metal complexing agent includes ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid, tetrasodium ethylenediaminetetraacetic acid and nitrilotriacetic acid.

11. The inhalation suspension preparation containing an SGC receptor agonist according to claim 10, characterized in that: The metal complexing agent is selected from disodium ethylenediaminetetraacetic acid; And / or, in the inhalation suspension preparation, the concentration of the metal complexing agent is 0.01 w / v%-1 w / v%.

12. The inhalation suspension preparation containing an SGC receptor agonist according to any one of claims 1 to 11, characterized in that: The riociguat or its pharmaceutically acceptable salt is in the form of micronized particles with an average particle size distribution range of 0.1-5 μm; And / or, in the inhalation suspension preparation, the concentration of riociguat or a pharmaceutically acceptable salt thereof is 0.05 mg / mL to 10 mg / mL; And / or, the mass median diameter (MMAD) of aerosol particles obtained by atomizing the inhalation suspension preparation is in the range of 1-10 μm.

13. The inhalation suspension preparation containing an SGC receptor agonist according to any one of claims 1 to 12, characterized in that: include: The concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.005 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.005 w / v%-0.05 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.01 w / v%-0.05 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.005 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Alternatively, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%-0.05 w / v%, Span 20 is 0.0005 w / v%-0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.005 w / v%-0.05 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Alternatively, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%-0.05 w / v%, citric acid-sodium citrate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%.

14. The inhalation suspension preparation containing an SGC receptor agonist according to any one of claims 1 to 13, characterized in that: The concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, Span 20 is 0.0005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, Span 20 is 0.005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, Span 20 is 0.0005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%, Span 20 is 0.001 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, Span 20 is 0.005 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 7-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, sodium dihydrogen phosphate-disodium hydrogen phosphate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, Span 20 is 0.0005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, Span 20 is 0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, Span 20 is 0.0005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%, Span 20 is 0.001 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, Span 20 is 0.005 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 20 is 0.05 w / v%, citric acid-sodium citrate is adjusted to pH 5-8, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Or, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.025 w / v%, citric acid-sodium citrate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%; Alternatively, the concentration of riociguat or a pharmaceutically acceptable salt thereof is less than 5 mg / ml and greater than 0 mg / ml, Tween 80 is 0.05 w / v%, citric acid-sodium citrate is adjusted to pH 5-9, NaCl is 0-1.5 mg / ml, and disodium EDTA is 0-0.1 w / v%.

15. The method for preparing an inhalation suspension preparation containing an SGC receptor agonist according to any one of claims 1 to 14, wherein: Take the micronized particles of riociguat, add the solution containing the pharmaceutically acceptable excipients for the suspension preparation, and mix.

16. Use of the inhalation suspension preparation containing an SGC receptor agonist according to any one of claims 1 to 14 in the preparation of a medicament for treating pulmonary hypertension (PH) disease.

17. The use according to claim 15, characterized in that Pulmonary hypertension (PH) diseases are classified according to the WHO, including but not limited to: Group 1 pulmonary hypertension - pulmonary arterial hypertension (PAH); or Category IV pulmonary hypertension - chronic thromboembolic pulmonary hypertension (CTEPH); or Category III pulmonary hypertension: pulmonary hypertension caused by respiratory diseases: pulmonary hypertension caused by chronic obstructive pulmonary disease (PH-COPD); or pulmonary hypertension caused by idiopathic interstitial lung disease (PH-ILD).

18. The use according to claim 16 or 17, characterized in that Including use in the preparation of pulmonary administration drugs for treating pulmonary hypertension (PH) diseases; Optionally, the pulmonary administration drug includes an inhalation aerosol, an inhalation powder inhalation, an inhalation liquid preparation and a preparation that can be converted into steam or an inhalation soft mist.

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