Inhalable pharmaceutical composition containing soluble guanylate cyclase receptor agonist, use thereof, and treatment method for pulmonary hypertension

Abstract

An inhalable pharmaceutical composition containing a soluble guanylate cyclase (SGC) receptor agonist, and a use thereof. The present invention can reduce the hypotensive side effects caused during administration, allows blood pressure to rapidly return to a normal level after administration, and enables the SGC receptor agonist to enter blood more quickly, improving pharmacokinetic parameters such as Tmax; and under specific formulations and instrument combinations, a pulmonary deposition rate can reach 40% or above.

Description

An inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist and uses thereof and methods of treating pulmonary arterial hypertension

[0001] Cross-reference to Related Applications

[0002] This application claims priority to the Chinese patent application No. 202411329039.8, filed on September 23, 2024, and entitled “An inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist and uses thereof”, the entire contents of which are incorporated herein by reference.

[0003] This application also claims priority to the Chinese patent application No. 202511342500.8, filed on September 18, 2025, and entitled “An inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist and uses thereof”, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0004] The present application relates to the field of pharmaceutical technology, in particular to an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist and uses thereof. BACKGROUND

[0005] Pulmonary arterial hypertension (PH) is a disease caused by abnormal elevation of pressure in the pulmonary arterial system. Unlike systemic hypertension, pulmonary arterial hypertension mainly affects the pulmonary arteries, and as the disease progresses, it further affects other pulmonary blood vessels such as pulmonary capillaries and pulmonary veins. Currently, there are clinically approved drugs for PAH (WHO Group I), chronic thromboembolic pulmonary arterial hypertension (CTEPH, WHO Group IV), and pulmonary arterial hypertension associated with interstitial lung disease (PH-ILD, WHO Group III) indications on the market. These drugs mainly target the three main signaling pathways in the pathogenesis of pulmonary arterial hypertension: prostacyclin, endothelin, and nitric oxide.

[0006] SGC receptor agonists belong to a class of drugs in the nitric oxide pathway, which can specifically bind and activate the oxidized, hemoglobin-free SGC form, thereby promoting the generation of cGMP, and is currently the only SGC receptor agonist drug approved for the treatment of pulmonary hypertension disease on the market. The overall adverse reaction rate of the riociguat treatment group compared with the placebo group was: headache (27% vs 13%), indigestion / gastritis (21% vs 8%), nausea (14% vs 11%), diarrhea (12% vs 8%), hypotension (10% vs 4%), and vomiting (10% vs 7%). The main adverse reactions of the riociguat drug Adempas (the original research drug is an oral tablet, currently with five dosage specifications of 0.5mg, 1.0mg, 1.5mg, 2.0mg and 2.5mg, and the oral dose is increased by 0.5mg every 2 weeks according to the actual tolerance of the patient) in clinical practice are gastrointestinal discomfort and hypotension. The side effect of hypotension is related to the systemic vasodilation effect of oral riociguat drug, and after actually taking the oral riociguat drug, the drug exposure in the lung tissue accounts for less than 2% of the total systemic drug exposure of riociguat (referring to the research results of the tissue distribution test of oral riociguat in the PMDA review document).

[0007] The only riociguat original research drug Adempas on the market is an oral dosage form, and there is no research report on inhaled riociguat dosage form. Based on the above-mentioned clinical side effects of oral riociguat drug, the application develops inhaled riociguat drug to deliver the drug directly to the pulmonary vessels, which can reduce the influence of the drug on other organs of the whole body, so as to reduce the gastrointestinal discomfort and hypotension adverse reactions in the process of treating pulmonary hypertension disease with riociguat drug. The relatively high drug concentration in the lung can maintain the same or better therapeutic effect as the oral original research drug. At the same time, compared with oral drugs, it can improve the pharmacokinetic parameters such as T max , so that the drug can be absorbed and take effect faster, rapidly relieve the symptoms of patients with pulmonary hypertension, and improve the compliance of treatment. SUMMARY

[0008] Based on the clinical application status of existing pulmonary hypertension disease drugs, and combined with the side effect defects disclosed by the prior art of riociguat, the present application focuses on developing an inhalable drug composition containing a soluble guanylate cyclase receptor agonist. The composition can deliver the SGC receptor agonist drug riociguat, which can play an effective therapeutic effect, to the target organ (pulmonary tissue) in the form of a safe and effective aerosol preparation, while significantly reducing the degree and incidence of systemic side effects of SGC receptor agonist drugs, such as hypotension and gastrointestinal discomfort. In addition, by directly delivering riociguat drugs to the lung tissue, it has been proven that less drugs can achieve the same or better therapeutic effect compared to oral treatment. As described in detail in the following application content, oral SGC receptor agonist drugs can cause a significant decrease in systemic blood pressure indicators such as systolic blood pressure SBP and diastolic blood pressure DBP, but lower doses of drugs in the lungs can significantly improve the situation of systemic blood pressure drop. The present application also unexpectedly found that pulmonary delivery of riociguat drugs can significantly improve T max pharmacokinetic parameters.

[0009] To this end, the present application provides the following technical solutions:

[0010] An inhalable drug composition containing a soluble guanylate cyclase receptor agonist, comprising:

[0011] an SGC receptor agonist or a pharmaceutically acceptable salt thereof; and

[0012] at least one inhalable aerosolizable excipient.

[0013] Optionally, the dosage form of the drug composition includes an inhalation aerosol, an inhalation powder aerosol, an inhalation spray aerosol, an inhalation liquid preparation, an inhalation soft mist aerosol, or a preparation that can be converted into a vapor;

[0014] Optionally, it is a suspension type inhalation aerosol.

[0015] Optionally, in the drug composition, the SGC receptor agonist or the pharmaceutically acceptable salt thereof is in the form of a particle or a solution;

[0016] and / or, the inhalable excipient includes a surfactant, a propellant, a dispersant and / or a suspending agent.

[0017] Optionally, when the SGC receptor agonist or the pharmaceutically acceptable salt thereof is in the form of a particle, the particle size distribution D50 thereof ranges from 0.1 to 10 μm;

[0018] Optionally, the particle size distribution D50 thereof ranges from 0.1 to 5 μm.

[0019] Optionally, the surfactant is selected from at least one of Tween 80, Tween 20, Span 20, Span 85, oleic acid, and phospholipid pharmaceutical excipients.

[0020] Optionally, the phospholipid pharmaceutical excipient comprises lecithin and / or distearoylphosphatidylcholine (DSPC).

[0021] Optionally, the surfactant is oleic acid.

[0022] Optionally, the surfactant is present in the pharmaceutical composition in an amount ranging from 0-5% wt.

[0023] Optionally, the propellant is selected from at least one of HFA-134a, HFA-152a, tetrafluoroethane, HFA-227ea, heptafluoropropane, and HFO-1234ze.

[0024] Optionally, the propellant is HFA-134a.

[0025] Optionally, the propellant is present in the pharmaceutical composition in an amount ranging from 50-99.9999% wt.

[0026] Optionally, the dispersing agent is selected from at least one of anhydrous ethanol, propylene glycol, polyethylene glycols, and water.

[0027] Optionally, the dispersing agent is anhydrous ethanol.

[0028] Optionally, the dispersing agent is present in the pharmaceutical composition in an amount ranging from 0-30% wt.

[0029] Optionally, the suspending agent is selected from polyvinylpyrrolidone (PVP) agents.

[0030] Optionally, the suspending agent is at least one of PVP (K25), PVP / 17 PF, and PVP (K30).

[0031] Optionally, the suspending agent is present in the pharmaceutical composition in an amount ranging from 0-5% wt.

[0032] Optionally, the SGC receptor agonist or pharmaceutically acceptable salt thereof comprises, but is not limited to, at least one of riociguat, vericiguat, and macitentan.

[0033] Optionally, the SGC receptor agonist or pharmaceutically acceptable salt thereof is riociguat.

[0034] Optionally, the content of SGC receptor agonist or its pharmaceutically acceptable salt in the pharmaceutical composition is 0.01-20%wt, the content of surfactant is 0-5%wt, the content of propellant is 50%-99.9999%wt, the content of dispersing agent is 0-30%wt, and the content of suspending agent is 0-5%wt; optionally, the content of propellant is 50%-99.99%wt.

[0035] Optionally, the content of SGC receptor agonist or its pharmaceutically acceptable salt in the pharmaceutical composition is 25-1000μg / pull.

[0036] Optionally, the inhalation device for the pharmaceutical composition is an inhalation device comprising a metering valve, a driver, an adapter, a nozzle, a canister, a counter and other necessary components.

[0037] Optionally, the spray hole of the driver has a diameter of 0.15-0.7mm and a length of 0.3-2mm.

[0038] Optionally, the spray hole of the driver has a diameter of 0.3-0.4mm and a length of 0.6-1.0mm.

[0039] Optionally, the spray parameters of the pharmaceutical composition meet at least one of the following conditions:

[0040] (1) the plume angle is 15-60°; optionally, the plume angle is 20-40°;

[0041] (2) the fine particle dose distribution FPF value is greater than 15%; optionally, the fine particle dose distribution FPF value is greater than 40%;

[0042] (3) the aerodynamic mass median diameter (MMAD) of aerosol particles is 1-10μm; optionally, the aerodynamic mass median diameter (MMAD) of aerosol particles is 1-5μm.

[0043] Optionally, the T max value of the pharmaceutical composition is 5min-30min.

[0044] A preparation method of the inhalable pharmaceutical composition containing soluble guanylate cyclase receptor agonist, comprising: preparing a pharmaceutically acceptable dosage form according to the formula.

[0045] Optionally, the dosage form comprises an inhalation aerosol, an inhalation powder aerosol, an inhalation spray aerosol, an inhalation liquid formulation, an inhalation soft mist aerosol, or a formulation that can be converted into a vapor; optionally, a suspension inhalation aerosol. Optionally, a prescribed amount of surfactant and / or suspending agent is dissolved in a dispersant, a prescribed amount of riociguat drug is added, the mixed dispersion is divided into aluminum cans, and a prescribed amount of propellant is filled into the cans through the valve installed on the cans.

[0046] The inhalable pharmaceutical composition comprising a soluble guanylate cyclase receptor agonist is used for any one of the following purposes:

[0047] (1) for the preparation of a drug for preventing and treating pulmonary arterial hypertension of the first type (WHO Group 1); the pulmonary arterial hypertension of the first type (WHO Group 1) includes arterial pulmonary arterial hypertension PAH (Pulmonary arterial hypertension);

[0048] (2) for the preparation of a drug for preventing and treating pulmonary arterial hypertension of the fourth type (WHO Group 4); the pulmonary arterial hypertension of the fourth type (WHO Group 4) includes chronic thromboembolic pulmonary hypertension CTEPH (Chronic thromboembolic pulmonary hypertension);

[0049] (3) for the preparation of a drug for preventing and treating pulmonary arterial hypertension of the third type (WHO Group 3); the pulmonary arterial hypertension of the third type (WHO Group 3) includes respiratory disease-induced pulmonary arterial hypertension diseases; the respiratory disease-induced pulmonary arterial hypertension diseases include pulmonary arterial hypertension PH-COPD (Pulmonary hypertension associated with chronic obstructive pulmonary disease) induced by chronic obstructive pulmonary disease; or, pulmonary arterial hypertension PH-ILD (Pulmonary hypertension associated with interstitial lung disease) induced by idiopathic interstitial lung disease.

[0050] The technical solution of the present application has the following advantages:

[0051] 1. The present application provides an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, comprising: a SGC receptor agonist or a pharmaceutically acceptable salt thereof; and at least one inhalable pharmaceutical excipient for aerosolization; in one aspect, the composition can be in the form of a safe and effective aerosol preparation, which delivers the SGC receptor agonist drug or its pharmaceutically acceptable salt (such as riociguat) to the target organ (pulmonary tissue) to exert effective therapeutic efficacy, and by directly delivering riociguat to the pulmonary tissue, it is proved that the same or better therapeutic effect can be achieved with less drug compared with oral treatment.

[0052] In another aspect, the inhalation of the SGC receptor agonist drug or its pharmaceutically acceptable salt can avoid contact with the gastrointestinal tract, thus reducing the incidence of adverse reactions of the gastrointestinal tract, and oral administration of the SGC receptor agonist drug can significantly reduce the systemic blood pressure indicators such as SBP and DBP, but the lower dose of pulmonary administration can significantly improve the systemic blood pressure decrease.

[0053] The present application also unexpectedly found that pulmonary delivery of the riociguat pharmaceutical composition of the present application can significantly improve the T max Pharmacokinetic parameters, the inhalation of the pharmaceutical composition can make the SGC receptor agonist enter the blood more quickly.

[0054] 2. The present application provides an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, wherein the SGC receptor agonist or its pharmaceutically acceptable salt is in the form of a particle or a solution; and / or, the inhalable pharmaceutical excipient includes a surfactant, a propellant, a dispersant and / or a suspending agent; the pharmaceutical composition provided by the present application contains a SGC receptor agonist drug and other inhalable pharmaceutical excipients, and under a specific prescription combination, the pulmonary deposition rate can reach more than 40%, with high stability and high compatibility, and higher FPF.

[0055] 3. The present application provides an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, wherein the driving device has a pore size ranging from 0.15 to 0.7 mm and a pore length ranging from 0.3 to 2 mm; alternatively, the driving device has a pore size ranging from 0.3 to 0.4 mm and a pore length ranging from 0.6 to 1.0 mm. The pharmaceutical composition provided by the present application is used with the above-mentioned spray device, and the pulmonary deposition rate can reach more than 40% with high stability. BRIEF DESCRIPTION OF DRAWINGS

[0056] In order to more clearly illustrate the technical solutions in the specific embodiments or prior art of the present application, the drawings needed to be used in the description of the specific embodiments or prior art will be briefly introduced. Obviously, the drawings in the following description are some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without any creative effort.

[0057] Figure 1 is the pharmacokinetic curve of each group in the embodiment 1 of the present application;

[0058] Figure 2 is the SBP of SD rats in each group in the experimental example 3 of the present application; the horizontal coordinate unit is h (hour), and the vertical coordinate unit is mmHg;

[0059] Figure 3 is the change value ΔSBP of systolic blood pressure of SD rats in each group in the experimental example 3 of the present application; the horizontal coordinate unit is h (hour), and the vertical coordinate unit is mmHg;

[0060] Figure 4 is the DBP of SD rats in each group in the experimental example 3 of the present application; the horizontal coordinate unit is h (hour), and the vertical coordinate unit is mmHg;

[0061] Figure 5 is the change value ΔDBP of diastolic blood pressure of SD rats in each group in the experimental example 3 of the present application; the horizontal coordinate unit is h (hour), and the vertical coordinate unit is mmHg;

[0062] Figure 6 is the detection results of right ventricular systolic pressure (RVSP), right ventricular function dp / dt(max), dp / dt(min), carotid artery blood pressure, and pulmonary artery pressure (mPAP) of SD rats in each group in the experimental example 4 of the present application;

[0063] Figure 7 is the microscope field photos of HE staining pathological sections of right heart tissue and lung tissue of SD rats in each group in the experimental example 4 of the present application;

[0064] Figure 8 is the comparative analysis results of the medial thickness of pulmonary arterioles of SD rats in each group in the experimental example 4 of the present application;

[0065] Figure 9 is the spray form of prescription 1 in the embodiment 5 of the present application;

[0066] Figure 10 is the spray form of prescription 2 in the embodiment 5 of the present application;

[0067] Figure 11 is the spray form of prescription 3 in the embodiment 5 of the present application;

[0068] Figure 12 is the spray form of prescription 4 in the embodiment 5 of the present application;

[0069] Figure 13 is the spray form of prescription 5 in the embodiment 5 of the present application. DETAILED DESCRIPTION

[0070] The following examples are provided to better enable those skilled in the art to further understand the application, and are not intended to limit the content and protection scope of the application, and do not constitute a limitation on the content and protection scope of the application. Any product that is the same or similar to the present application obtained by anyone under the inspiration of the present application or by combining the present application with other prior art features falls within the protection scope of the present application.

[0071] The specific experimental steps or conditions not mentioned in the examples can be carried out according to the conventional experimental steps described in the literature in the art or the operation or conditions. The reagents or instruments used are not specified by the manufacturer, and are conventional reagent products that can be obtained by purchase.

[0072] Riociguat:

[0073] Riociguat is an innovative soluble guanylate cyclase agonist for the treatment of CTEPH (inoperable or persistent / recurrent after surgery) or PAH (Reference: Rare Disease Diagnosis and Treatment Guidelines 2019 Edition). The drug has been designated as an orphan drug by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA). It has a positive effect on improving patient exercise capacity, WHO functional classification, and pulmonary hemodynamic parameters, etc. Most of its adverse reactions can be attributed to its vasodilator mechanism. Then, due to the serious bleeding and fetal hazards of the drug, riociguat is contraindicated in pregnant women.

[0074] The chemical structural formula of riociguat is as follows:

[0075] CAS No.: 625115-55-1.

[0076] The molecular weight of riociguat is 422.4 g / mol, which is a white or light yellow solid powder. The solubility in water at 25℃ is 4 mg / L, the melting point is 247-251℃, and the solubility can be significantly improved under low pH conditions.

[0077] SGC receptor agonist drugs:

[0078] One of the most widely accepted effects of SGC agonist drugs is their action on the NO / cGMP signaling pathway to dilate blood vessels. In some preclinical animal tests, SGC agonist drugs have been shown to have a dose-dependent effect on lowering blood pressure, with the effect being more pronounced at higher drug doses, and in some cases, showing side effects of hypotension. Given the prevalence of hypotension as a side effect of SGC agonist drugs during disease treatment, the inhalable SGC agonist drug composition provided by the present application can improve the side effect of hypotension to some extent, as described in the embodiments of the present application (in the experiment of monitoring the blood pressure level of SD rats under the condition of pulmonary administration compared with oral administration).

[0079] SGC (soluble guanylate cyclase):

[0080] is a heterodimeric protein composed of α and β subunits, with the β subunit containing a heme group. NO binds to the heme on SGC, inducing a conformational change that activates the catalytic domain of the enzyme, promoting the production of cGMP. Riociguat does not depend on NO and can directly bind to the α subunit of SGC, enhancing the catalytic activity of the enzyme and thus increasing the production of cGMP.

[0081] Inhalable composition in the form of an aerosol:

[0082] The present application provides a pharmaceutical composition containing a riociguat component suitable for administration by inhalation, which composition is in the form of an aqueous solution, an aqueous suspension, a dry powder, or a mixture of one or more pharmaceutically acceptable propellants or carriers, or a preparation in which riociguat is encapsulated in liposomes or other material matrix. In view of the above-mentioned practical situation, the content of the present application can be realized in the following embodiments, in which the pMDI technology is used to deliver the composition containing the riociguat pharmaceutical component.

[0083] pMDI formulation technology:

[0084] pMDI formulations mainly rely on the propulsive force generated by the propellant system to eject the drug formulation from the device in a form that can be inhaled by the patient. The propellant is usually composed of HFA (liquefied hydrofluoroalkane) which is screened to provide the required vapor pressure and stability for the formulation. The current pMDI formulation usually consists of: the drug active ingredient, one or more propellants, and other optional pharmaceutical excipients such as co-solvents, surfactants, suspending agents, and lubricants, etc. The drug active ingredient of the formulation in the pMDI device is generally present in the form of fully dissolved or particulate suspended in the liquefied propellant system. But most of the drug active ingredients are not sufficiently soluble in the propellant, even with the addition of co-solvents such as ethanol, they cannot be fully dissolved in the formulation. The MMAD of the pMDI aerosol spray must be strictly controlled to be less than 10 μm, so that the drug can enter the lungs. The MMAD parameter control of the solution type aerosol formulation is more difficult than that of the particulate suspension type (the solvent evaporation rate will affect the particle size of the droplets), so the formulation with drug particles suspended in the propellant is more preferred.

[0085] pMDI inhalation device:

[0086] The complete pMDI dosage form is composed of two parts of prescription and drug delivery system, and the drug delivery system is composed of three parts of pressure-resistant container, metering valve system and driver. The drug delivery system, i.e. the pMDI inhalation device, as a key component of the pMDI dosage form, is crucial to the performance of the drug in the in vitro deposition prediction experiment (ACI and NGI experiment), and also directly affects the deposition amount of the drug in the lung and respiratory tract to exert the therapeutic effect. The drug delivery system also needs to combine the pathological site characteristics of the indication of the drug (systemic drug treatment by alveolar absorption into blood, or a specific pathological site such as upper respiratory tract, lower respiratory tract, distal site of respiratory tract and alveoli), to form differentiated spray form and particle size distribution characteristics, and to reduce the deposition of the drug in the oral cavity and throat as a whole.

[0087] The formulation of the application is filled into a container which can withstand the vapour pressure of the HFA propellant, such as plastic, coated glass bottles, or more preferably metal canisters. Metal canisters include, in particular, stainless steel canisters and aluminium canisters which have been anodised or treated with an organic coating. The metering valve used in the application is selected to have a volume which is designed to deliver the prescribed amount per actuation. The valve gasket is made of any suitable elastomeric material which prevents leakage of the propellant, such as low density polyethylene and rubber. The valve seal, including the gasket seal and the seal around the metering chamber, is made of an inert material which does not degrade in reaction with the formulation of the application. Suitable canisters, metering valves, valve gaskets, valve seals, valve stems and the like can also be purchased from aerosol device manufacturers. The material composition of the inhaler device used is selected to meet the compatibility requirements for chemical stability, physical stability and mechanical handling stability with the inhalable composition prepared.

[0088] According to the prior art references, changing the driver orifice parameters affects the plume angle, plume velocity and plume duration of the pMDI, and further affects the quality attributes of the lung deposition of the drug, such as higher FPF and lower throat deposition. The prior art documents indicate that the orifice length of the commercialized suspension MDI products varies in the range of 0.5-1.5 mm, and the orifice diameter is generally greater than 0.3 mm. The prior art does not suggest that the riociguat suspension inhalation aerosol formulation can be effectively delivered by the pMDI technology using the conventional or non-conventional size parameters.

[0089] As used herein, T max The value represents the time to peak concentration of the blood plasma, i.e. the time required for the drug to reach the maximum blood plasma concentration after entering the human body.

[0090] As used herein, C max The value (ng / h) represents the concentration of the drug when it reaches the highest concentration in the human body, and is an important pharmacokinetic parameter which can reflect the absorption of the drug in the human body.

[0091] As used herein, D10 represents that 10% of the particle diameters are less than or equal to this value, D50 represents that 50% of the particle diameters are less than or equal to this value, and D90 represents that 90% of the particle diameters are less than or equal to this value.

[0092] As used herein, HFA-134a, HFA-152a, tetrafluoroethane, HFA-227ea, heptafluoropropane and HFO-1234ze are all commercially available products.

[0093] As used herein, PVP (K25), PVP / 17 PF and PVP (K30) are all commercially available products.

[0094] As used herein, a press represents a dose, and a press represents a press of a dose of a spray device.

[0095] Experimental Example 1: Pharmacokinetic experiment of pulmonary administration versus oral administration

[0096] Twenty-four SD rats (specification weight 240-260 g, age about 10 weeks) were purchased, and divided into 8 groups with 3 SD rats in each group. After adaptive feeding for 1 week, the SD rats in groups 1, 2, and 3 were administered with a solution of riloxigoue (concentrations were 0.3 mg / ml, 0.2 mg / ml, and 0.1 mg / ml, respectively, and the solvent was physiological saline containing 10% wt ethanol) through the oral cavity into the laryngeal tube using a Microsprayer spray device (purchased from Shanghai Yuyan Scientific Instrument Co., Ltd.), and the pulmonary administration was performed once at a dose (the dose of riloxigoue) of 0.24 mg / kg, 0.16 mg / kg, and 0.08 mg / kg, respectively. The “dose” refers to the dose of riloxigoue, which is calculated according to the weight (Kg) of the rat. The dose of riloxigoue was determined, and the volume of administration was determined by the concentration of the solution (for example, 0.3 mg / ml, 0.2 mg / ml, 0.1 mg / ml, etc.). The SD rats in groups 4, 5, 6, and 7 were administered with a suspension of riloxigoue (the riloxigoue micropowder in Example 1, Table 6, No. 5, 25 mg and 15 mg were accurately weighed and added into 10 mL of a dispersion medium (physiological saline solution containing 0.05% wt Tween 80), and the suspension was prepared by fully dispersing and mixing to obtain a suspension with a concentration of 2.5 mg / mL and 1.5 mg / mL, respectively, and the pulmonary administration was performed using the Microsprayer spray device at a dose (the dose of riloxigoue) of 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg, respectively. The SD rats in group 8 were administered with a dispersion of the original riloxigoue tablet ground into powder (the grinding process in Example 1, No. 5), and the suspension was prepared by fully dispersing the original riloxigoue tablet ground powder in physiological saline to obtain a suspension with a riloxigoue concentration of 2.5 mg / mL and 5 mg / mL (the volume of administration was calculated according to the weight of the rat and the dose), and the oral gavage administration was performed at a dose (the dose of riloxigoue) of 10 mg / kg. Blood samples were collected at 0.1 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 7 h, and 24 h after the administration of the SD rats in each group, and the supernatant was obtained after the blood samples were fully centrifuged and detected for the drug content. The pharmacokinetic parameter results obtained after the blood samples were detected by LC-MS are shown in the following table and Figure 1. It can be seen that the T max value of oral riloxigoue is 30 min, and the Tmax The value is 5 min to 30 min, indicating that the inhalation administration is more rapid, further indicating that the specific particle size of the riociguat raw material powder provided in the present application is good in the dissolution and absorption of the drug particles deposited in the lung tissue after being delivered into the lung by the pulmonary administration device, and is directly reflected in the T max parameters. Further, the specific particle size of the riociguat raw material provided in the present application, by means of the propellant system of the aerosol, forms an aerosol containing drug particles, and can also achieve similar absorption into blood through oral inhalation into the lung, and is directly reflected in the T max parameters.

[0097] Table 1, pharmacokinetic parameter results of each group

[0098] Experimental Example 2: Lung deposition rate experiment of Microsprayer device administration compared with tracheal minimally invasive administration

[0099] In the administration of the seventh group of SD rats in Experimental Example 1, the Microsprayer device was used for administration through the trachea into the lung, and the administration dose was 4 mg / kg. After 15 min of administration, the SD rats were anesthetized and dissected, and it was found that a large amount of drug particles were also deposited in the laryngeal tube and trachea. Subsequently, the laryngeal tube was cut off, and the lung tissue below the trachea was collected, and the weight (mg) of the lung tissue was accurately measured. The lung tissue was homogenized using a homogenate solution (homogenate solution preparation method: 2.5 mL of 17% H3PO4, 2 g of ascorbic acid were added to 100 mL of 50% acetonitrile (containing 0.1% formic acid) solution, and then mixed thoroughly), and the drug content of the homogenate solution was detected by LC-MS analysis. The theoretical drug lung deposition rate after administration was calculated according to the calculation method of: lung tissue riociguat drug content ÷ total amount of riociguat in actual administration × 100%. Further, the SD rats were administered through the tracheal minimally invasive site by the tracheal minimally invasive method, and the drug was administered through the trachea and lung lobe connection into the lung. The theoretical drug lung deposition rate after administration was calculated in the same way as above. The theoretical drug lung deposition rate of the two lung administration methods is shown in the following table. It can be concluded that about 40% of the drug particles in the suspension prepared in the present application are deposited in the lung tissue by using the Microsprayer device to administer the drug through the trachea into the lung. By using the tracheal minimally invasive surgery to administer the drug through the trachea and lung lobe connection into the lung, about 100% of the drug particles in the suspension provided in the present application are deposited in the lung. The latter administration method is more accurate in dose calculation, and has fewer external interference factors, so it is preferred in the riociguat toxicity experiment of Experimental Example 3 of the present application. However, the pharmacodynamic experiment in Experimental Example 4 needs to be carried out for 14 days of continuous administration, and the continuous tracheal minimally invasive surgery causes greater trauma to the experimental animals, so the former administration method is preferred in Experimental Example 4.

[0100] Table 2: Theoretical lung deposition rate of the drug for two pulmonary administration methods

[0101] Experimental Example 3: Riociguat Toxicology Experiment

[0102] The experimental process includes: after the tracheal minimally invasive surgery, the drug is administered by spraying into the tracheal opening of the lung, and the blood pressure of the SD rats is measured by using the Softron intelligent non-invasive blood pressure meter BP-2010A. The SBP and DBP display values of the rats in the device at the time points of 0 h, 0.5 h, 1.5 h, 4 h and 24 h are read respectively, and the blood pressure changes of the SD rats under the conditions of pulmonary administration and oral administration are compared. The animal experiment grouping and administration are as follows:

[0103] 1) Oral administration dose 10 mg / kg, the administration sample is a dispersion solution prepared from the 2.5 mg specification riociguat original research tablet (same as in Experimental Example 1); 5 SD rats (specification weight 240-260 g, age about 10 weeks);

[0104] 2) Pulmonary administration dose 1.5 mg / kg and 4 mg / kg, the administration sample is a prepared riociguat suspension (the blank solvent is a physiological saline solution containing 0.05%wt Tween 80, the riociguat micropowder is prepared according to the implementation scheme No. 5 in Example 1, and the riociguat micropowder is dispersed in the blank solvent to prepare a suspension with a riociguat mass concentration of 2.5 mg / mL and 5 mg / mL (the administration volume is calculated according to the rat weight and the administration dose); 5 SD rats (specification weight 240-260 g, age 10 weeks);

[0105] 3) The blank group for pulmonary administration is the same volume of solvent (0.05%wt Tween 80 physiological saline solution) in 2); 5 SD rats (specification weight 240-260 g, age 10 weeks);

[0106] As shown in Figures 2-5, the SBP and DBP blood pressure monitoring of the SD rats in each group within 24 h after oral administration of 10 mg / kg, pulmonary administration of 1.5 mg / kg, 4 mg / kg and administration of blank solvent is shown. It can be concluded that pulmonary administration can effectively reduce the risk of hypotension side effects during riociguat treatment and quickly restore normal blood pressure levels; compared with oral administration of the same drug efficacy, after inhalation administration, ΔSBP (systolic blood pressure SBP variable / reduction) can be reduced by 15%-100%, ΔDBP (diastolic blood pressure DBP variable / reduction) can be reduced by 15%-100%, and the blood pressure recovery time can be shortened by 1-4 h. max max ​The time ΔDBP (diastolic blood pressure DBP variable / reduction) can be reduced by 15% to 100%, indicating that the blood pressure recovers quickly after inhalation administration. C max The time period of 5 min to 30 min is the lung administration T max The value of 5 min to 30 min can correspond to the horizontal coordinates 5 min to 30 min in FIGS. 2-5.

[0107] Further, the working principle of the suspension inhalation aerosol is that the propellant serves as a power to atomize other raw and auxiliary materials of the suspension inhalation aerosol to form an aerosol (atomized particles). After the aerosol carries the drug particles into the lung tissue, the drug particles are deposited and dissolved in the lung, and are absorbed by the lung tissue. According to the above mechanism, the tracheal minimally invasive tracheal oral spray administration into the lung is used in the animal study of the inhalation preparation to perform the toxicology test. In order to ensure that the lung absorption mechanism of the suspension inhalation aerosol of the present application is the same, the drug particle morphology in the administration sample of the present experiment is set to be the same as the particle morphology of the suspension inhalation aerosol of the present application, so that the pharmacological and toxicological test can be used to verify the rationality of the lung absorption of the suspension inhalation aerosol of the present application. Therefore, it can be concluded from the present experimental example that the blood pressure can be completely recovered within 24 h after the inhalation use of the suspension inhalation aerosol provided by the present application, while there is still hypotension after oral administration for 24 h.

[0108] Experimental Example 4: Riociguat pharmacodynamics experiment

[0109] By the method of subcutaneous injection of monocrotaline (dose of 60 mg / kg), 16 SD rats (specification of 240-260 g in weight and 10 weeks in age) of a pulmonary arterial hypertension pathological model were successfully induced, and then they were randomly divided into groups: G1 model group (n=4+2), G2 administration group (n=4+2), and G3 positive drug group (n=4) in total 3 groups. Among them:

[0110] The G1 (or recorded as G1-Vehicle) group was administered with 100 μL of blank solvent (physiological saline solution containing 0.05% wt Tween 80) by the Microsprayer device for lung administration;

[0111] The G2 (or recorded as G-BAY 63-2521) group was administered with 100 μL of a dispersion liquid containing Riociguat drug particles (blank solvent was physiological saline solution containing 0.05% wt Tween 80, Riociguat particle powder was prepared according to the implementation scheme No. 5 in Experimental Example 1, and the Riociguat particle powder was dispersed in the blank solvent to prepare a Riociguat suspension with a mass concentration of 2.5 mg / mL and 5 mg / mL (the administration volume was calculated according to the rat weight and the administration dose)) by the Microsprayer device for lung administration at a dose of 4 mg / kg;

[0112] G3 (or noted as G3-positive drug) group was administered with 2.5 mg size of Gilotrif tablet (same as in Experimental Example 1) by gavage at a dose of 10 mg / kg.

[0113] After the treatment of the above groups for 14 days, the rats were anesthetized and the right heart catheter was inserted to detect: RVSP, right ventricular function dp / dt(max), dp / dt(min), carotid arterial blood pressure, mPAP; after the rats were dissected, the lung and right heart tissues were taken for pathological analysis, and the medial thickness of the pulmonary arterioles of the rats in each group was compared. The specific experimental grouping and administration are shown in the following table:

[0114] (Note: According to the difference between the lung administration and tracheal minimally invasive administration of the Microsprayer device in Experimental Example 2, the lung administration dose of 4 mg / kg in the G2 group in this experiment is basically the same as the lung administration dose of 1.5 mg / kg in Experimental Example 3.)

[0115] Table 3, experimental grouping and administration

[0116] The detection results of the indicators of RVSP, right ventricular function dp / dt(max), dp / dt(min), carotid arterial blood pressure, mPAP of the rats in the G1, G2 and G3 groups are shown in Figure 6. It can be concluded that the mPAP of the oral administration (10 mg / kg / day) dose group (G3) changed from 30.06 mmHg to 31.37 mmHg compared with the pathological model group (G1), while the pulmonary administration group (4 mg / kg / day) (G2) decreased to 26.5 mmHg; the average value of RVSP of the oral administration (10 mg / kg / day) treatment group decreased from 28.47 mmHg to 18.65 mmHg compared with the pathological model group, and the pulmonary administration group (4 mg / kg / day) decreased to 21.38 mmHg.

[0117] The microscope field photos of the HE staining pathological sections of the right heart and lung tissues of the rats in the G1, G2 and G3 groups are shown in Figure 7. It can be concluded that the right ventricular myocardial cells of the rats in the pathological model group were hypertrophic and arranged in disorder, while the right ventricular myocardial cells of the pulmonary administration group / oral administration group were relatively uniform in size and arranged in order; the vascular cavity of the pulmonary arterioles of the rats in the pathological model group was obviously narrowed, and the smooth muscle was obviously proliferated and hypertrophic, and the pathological changes of the pulmonary arterioles were alleviated after the pulmonary administration and oral administration treatment.

[0118] G1, G2 and G3 group rats: the results of comparative analysis of the pulmonary arteriole media thickness are shown in Figure 8. It can be concluded that the average media thickness of the pulmonary arteriole of the pathological model group is 18.52 μm, the oral (10 mg / kg / day) treatment group is reduced to 11.21 μm (p<0.01), and the pulmonary administration group (4 mg / kg / day) is reduced to 9.44 μm (p<0.001).

[0119] Further, the working principle of the suspension inhalation aerosol is that the propellant serves as a power to atomize other raw and auxiliary materials of the suspension inhalation aerosol to form an aerosol (atomized particles). After the aerosol carries the drug particles into the lung tissue, the drug particles are dissolved and absorbed by the lung tissue. According to the above mechanism, the Microsprayer pulmonary administration device commonly used in animal research of inhalation preparations is used for administration in the toxicological test. In order to ensure the same pulmonary absorption mechanism as the suspension inhalation aerosol of the present application, the drug particle morphology in the administration sample of the present experiment is set to be the same as the particle morphology of the suspension inhalation aerosol of the present application, so that the drug efficacy test can be used to verify the rationality of the pulmonary absorption of the suspension inhalation aerosol of the present application. It can be concluded from the present experimental example that the suspension inhalation aerosol provided by the present application can be used for treating pulmonary arterial hypertension.

[0120] Experimental Example 5: Screening of riociguat inhalation dosage forms

[0121] 1. Solution-type atomized inhalation liquid preparation

[0122] One embodiment of the present application is to prepare a solution-type riociguat atomized inhalation liquid preparation. In the present embodiment, a riociguat solution dosage form is prepared according to a 0.2 mg / mL dosage specification, the pH of the solution system is controlled to be 4 and 7, and a certain amount of solubilizing excipients is added to investigate the feasibility of preparing a riociguat solution dosage form. The prescription preparation method is as follows:

[0123] 0.2 g of riociguat raw material was accurately weighed into a 1000 mL volumetric flask to prepare a riociguat solution with a theoretical concentration of 0.2 mg / mL. The influence variables of the solution system prepared were controlled as follows: the pH value was 4 or 7; a certain amount of solubilizing surfactant pharmaceutical excipients was added or not; different contents of solubilizing surfactant pharmaceutical excipients. The specific prescription design is shown in the following table:

[0124] Table 4, prescription of riociguat solution preparation

[0125] In this embodiment, a solution preparation of 0.2 mg / mL concentration of riociguat is to be prepared. According to the riociguat FDA review document, the solubility of riociguat in water solution at 25°C is 4 mg / L, and it is difficult to prepare a solution of 0.2 mg / mL concentration of riociguat in aqueous solution. Subsequently, in this embodiment, the pH of the aqueous solution is adjusted to 4, and the solubilizing surfactant pharmaceutical excipients commonly used in inhalation dosage forms (referring to the list of DMF inhalation pharmaceutical excipients on the FDA website) such as oleic acid, Tween 80, Tween 20 and polyethylene glycol are added to the aqueous solution. None of them can obtain a solution of 0.2 mg / mL concentration of riociguat, indicating that due to the limitation of the solubility properties of riociguat drug itself, it is difficult to prepare a solution type preparation for aerosol inhalation.

[0126] 2. Solution type inhalation aerosol

[0127] In one embodiment of the present application, the active ingredient of riociguat is fully dissolved in an organic solvent such as ethanol to form a solution, other pharmaceutical excipients such as surfactants are added to the solution, and the final prepared solution is filled into an aerosol canister with a metering valve, and a propellant such as HFA134a is filled into the canister through the metering valve to prepare a solution type inhalation aerosol. In this embodiment, a 100 μl volume valve is selected to prepare a solution type inhalation aerosol, and a theoretical drug concentration of 200 μg / pull is designed, which requires the drug to meet the solubility requirement of more than 2 mg / mL in the propellant system. According to the riociguat FDA specification document, the solubility of riociguat in ethanol solvent is 800 mg / L, and the riociguat drug substance is insoluble in the propellant. If the mass fraction of ethanol in the propellant system is 30%, 24 μg / pull can be achieved, and 5 pulls can achieve the therapeutic effect. However, 30% ethanol concentration has lung toxicity, so it is not feasible. When the ethanol content is reduced to 15%, the ethanol content is still 12 μg / pull, which still has lung toxicity. When the ethanol content is 10%, the lung toxicity is lighter, but the dose of 8 μg / pull cannot achieve the therapeutic effect. In this embodiment, the survival rate and physiological condition of SD rats during lung administration of solutions with different ethanol mass fractions are investigated, and the experimental conditions of 20 SD rats evenly divided into 4 groups (5 rats / group) are as follows:

[0128] Table 5. Survival rate and physiological condition of SD rats during lung administration of solutions with different ethanol mass fractions

[0129] From the above, it can be concluded that both solution type aerosol inhalation liquid preparation and solution type inhalation aerosol are difficult to be applied to riociguat inhalation dosage form.

[0130] Example 1: Control of particle size of raw material

[0131] Due to the limitation of the solubility of the raw material of riociguat (see the exploratory study in Experimental Example 5), it is difficult to develop a solution inhalation dosage form. Therefore, the drug can be alternatively prepared into drug particles of a particle size and surface morphology, and the drug particles are aerosolized and inhaled into the lungs through the nose and mouth to exert a therapeutic effect. In the treatment of pulmonary hypertension, the deposition of the aerosol containing drug particles at the correct target lesion in the respiratory system is of great significance to maximize the therapeutic effect and reduce side effects. In general, the smooth muscle cells of the pulmonary artery and small arteries, and the vascular endothelial cells in the lung tissue are ideal therapeutic targets for pulmonary hypertension. The particle size distribution of the raw material particles plays a key role in the ideal deposition of the particles in the aerosol in the lungs.

[0132] One technical solution for controlling the particle size of the raw material in the present application is to dissolve the riociguat drug in an organic solvent, or to add a certain amount of amino acid pharmaceutical excipients such as leucine, glycine and aspartic acid; sugar pharmaceutical excipients such as trehalose and mannitol; PVP and carboxymethyl starch, etc. in the organic solvent. The prepared drug-containing solution is treated by a spray drying device, and the solution is atomized into droplets by nitrogen and rapidly evaporated in hot air to remove the water in the droplets to obtain dry drug particles. The particle size distribution of the finally formed drug particles is controlled by adjusting the parameters such as the feeding rate, air flow rate and temperature during the spray drying process. These preparation processes can produce amorphous drug particles, which can improve the solubility, especially for poorly soluble drugs such as riociguat, which can improve the bioavailability, or improve the dissolution and release behavior of the drug after inhalation, and improve the drug utilization in the lung tissue.

[0133] One technical solution for controlling the particle size of the raw material in the present application is to use an air flow mill to crush the riociguat raw material, and by controlling the crushing parameters such as the inlet pressure, crushing pressure and feeding amount, to obtain raw material micropowder of a desired particle size. The following table shows the air flow milling test conditions and particle size results of the riociguat micropowder prepared in the laboratory:

[0134] Table 6, Air flow milling test conditions and particle size results of riociguat micropowder

[0135] The raw material drug particle size D50 after jet milling in the table is less than 5 μm, which meets the requirements for preparing multiple batches of suspension type riociguat aerosol samples, but the embodiments in the present application are not limited to using the raw material drug powder with D50 less than 5 μm listed in the above table. Some embodiments also include selecting raw material drugs with D50 less than 7 μm or D50 less than 10 μm to prepare samples, and finally whether the fine particle drug dose ratio (FPF) value of the aerosol samples prepared from raw material drugs with different particle size distributions meets the FPF limit in the national pharmacopoeia standard to limit the raw material drug particle size distribution requirement in the substantial protection of the present application, which is 0.1 μm < D50 < 10 μm.

[0136] Example 2: Preparation of riociguat suspension type inhalation aerosol

[0137] One embodiment of the present application is to prepare riociguat inhalation aerosol. In this embodiment, the riociguat raw material drug particles prepared according to the implementation scheme No. 5 in Example 1 are used. The riociguat raw material drug particles and propellant are placed in a premixing tank and fully mixed uniformly by high-speed stirring. The mixed drug is pressurized into an aerosol device through an overpressure filling device to prepare riociguat inhalation aerosol. In this embodiment, according to different prescription design requirements such as: drug content per puff, different types and amounts of surfactants, dispersant amount, and suspension aid type and amount requirements, the components are dosed and prepared according to the different mass ratios of each component to prepare the corresponding prescriptions, and these prescriptions are filled into inhalation devices with different spray hole diameters / length parameters. According to the requirements of the 2020 version of the Chinese Pharmacopoeia (Volume IV) General 0951 Inhalation Preparation Fine Particle Aerodynamic Characterization Determination Method, the Andersen cascade impactor (ACI) device is used to evaluate the aerodynamic particle size distribution of the prepared riociguat inhalation aerosol samples to evaluate whether the prepared aerosol samples meet the expected lung deposition characteristics.

[0138] Formulation process:

[0139] The prescription amount of surfactant and suspension aid pharmaceutical excipients are dissolved in the dispersant. After fully stirring and dissolving, the prescription amount of riociguat drug particles (No. 5 particles in Table 6 in Example 1) is added, and the stirring speed is controlled at 4000 rpm and the stirring time is 5 min. The fully mixed dispersion is divided into aluminum cans, and the prescription amount of propellant selected from HFA-134a is filled through the valve installed on the can body. 100 bottles of riociguat suspension type inhalation aerosol with a theoretical drug amount of 100 μg / puff and 200 μg / puff are prepared (in the actual preparation process, 25% excess raw material drug is required to reach the rated injection drug amount per puff). The following table shows the prescription composition of 100 bottles of riociguat inhalation aerosol and the spray hole diameter / length characteristic parameters of the inhalation device according to the above preparation method:

[0140] Table 7. Formulation composition of the aerosol inhalation of Rilapladib and the orifice diameter / length characteristics of the inhalation device

[0141] Experimental procedure for ACI device to detect fine particle dose:

[0142] After ensuring the Anderson Cascade Impactor (ACI) device is clean, the prepared Rilapladib aerosol is connected to the throat of the ACI device via the interface. After setting the detection flow rate (usually 28.3 L / min), the aerosol is sprayed five times to ensure that enough samples are collected in the ACI device for detection and analysis. The collection port, throat, deposition plates and filter test assembly components are thoroughly washed with 50 mL of methanol solvent to collect the drug. The collected samples from each part are analyzed using high performance liquid chromatography (HPLC) to determine the amount of drug deposited on each test component. The amount of drug deposited on each test component (in μg / puff) is input into the analysis software program, which outputs the aerodynamic particle size distribution parameters such as MMAD, geometric standard deviation (GSD) and FPF of the aerosol. The amount of drug deposited in each component of the ACI device for Rilapladib aerosol samples with formulation numbers 1-5 is shown in the following table:

[0143] Table 8. Amount of drug deposited in each component of the ACI device for Rilapladib aerosol samples

[0144] The MMAD, GSD and FPF values output by the analysis software after inputting the drug content detection values of each component in the ACI experiment for formulations 1-5 are shown in the following table. According to the Chinese Pharmacopoeia Inhalation Preparation Fine Particle Aerodynamic Characteristics Determination Method (General Rule 0951), the FPF should not be less than 15% of the labeled dose:

[0145] Table 9. MMAD, GSD and FPF values output by the analysis software after inputting the drug content detection values of each component in the ACI experiment

[0146] Example 3. Investigation of the compatibility of Rilapladib bulk drug with ethanol:

[0147] The following table shows the change in impurity content of Rilapladib bulk drug mixed with ethanol solvent at a mass ratio of 1:1 under the conditions of 25°C / 60% RH and 40°C / 75% RH. It can be seen that the compatibility of Rilapladib bulk drug with ethanol solvent is stable.

[0148] Table 10. Investigation of the compatibility of Rilapladib bulk drug with ethanol

[0149] Example 4 Stability study of the aerosol samples of olokizumab

[0150] The changes in impurity content of the aerosol samples of olokizumab of prescription numbers 1, 2, and 3 in Example 2 were stored at 25°C / 60% RH and 40°C / 75% RH, as shown in the following table:

[0151] Table 11, Aerosol samples of olokizumab of the prescription

[0152] Example 5 Comparison of the aerosolization patterns of the suspension aerosol of olokizumab

[0153] The spray pattern of an inhalation aerosol product can directly affect the distribution and deposition of the drug in the respiratory tract, and it is important to evaluate the spray pattern to determine whether the inhalation aerosol product has effectively delivered the drug and achieved good therapeutic effect. The inhalation aerosol product is a combination of a drug and a device, and the component parameters in the driver assembly of the aerosol device, i.e., the orifice diameter and the orifice length, can directly affect the spray model of the inhalation aerosol product. By optimizing these parameters to improve the spray pattern, the efficiency of drug delivery and the quality of the product can be improved. In this embodiment, the prescriptions prepared in Example 2 were used as the research object, and different aerosol device driver parameters were set. Specifically, the driver parameters for prescriptions 1-3 in Example 2 were: orifice diameter 0.35 mm / orifice length 0.7 mm; and the driver parameters for prescriptions 4-5 were: orifice diameter 0.30 mm / orifice length 1.0 mm. After setting the trigger parameters, camera parameters, and laser parameters in the spray pattern analyzer (produced by Proveris, USA), the images collected by the spray pattern analyzer were processed by Viora software, and the parameters describing the spray pattern characteristics, such as jet velocity, jet angle, and plume duration, were analyzed and calculated. The specific spray patterns of prescriptions 1-5 in Example 2 collected in this embodiment are shown in the following table, and exemplary images are provided in Figures 9-13.

[0154] Table 12, Spray patterns of each prescription

[0155] Note: 30mm height means the spray test was performed at a distance of 30mm from the detector and the spray area was measured. 60mm height means the spray test was performed at a distance of 60mm from the detector and the spray area was measured. 60mm distance means the spray test was performed at a distance of 60mm from the detector and the spray fan angle and the atomization pattern were measured. Dmin means the smallest diameter of the atomization area, Dmax means the largest diameter of the atomization area, Area means the atomization area, Arm1 means the upper separation angle of the atomization fan (the angle between the upper edge of the fan and the horizontal line in the middle of the fan), Arm2 means the lower separation angle of the atomization fan (the angle between the lower edge of the fan and the horizontal line in the middle of the fan), angle means the total angle of the atomization fan, width means the maximum vertical width of the atomization fan.

[0156] The above results of the detection of the atomization pattern of the aerosol are used to determine the influence of different formulations and devices on the atomization pattern of the aerosol.

[0157] Example 6: Preparation of a suspension type inhalation aerosol of riociguat

[0158] The prescription amount of surfactant and suspending agent pharmaceutical excipients were dissolved in the dispersant, after fully stirring and dissolving, the prescription amount of riociguat drug particles (No. 5 particles in Table 6 in Example 1) was added, the stirring speed was controlled at 4000 rpm, and the stirring time was 5 min. The fully mixed dispersion was divided into aluminum cans, and the prescription amount of propellant was filled through the valve installed on the can body, and the propellant was selected from HFA-134a, HFO-1234ze and HFA-152a. 100 bottles of riociguat suspension type inhalation aerosol with a theoretical drug amount of 100 μg / puff and 200 μg / puff were prepared (in the actual preparation process, 25% excess of raw drug was included to reach the rated injection drug amount per puff), as shown in Table 13 below, the prescription composition of 100 bottles of riociguat inhalation aerosol and the orifice diameter / length characteristic parameters of the inhalation device according to the above preparation method; Table 14 is the MMAD, GSD and FPF parameters detected by the ACI device detection fine particle dose experiment corresponding to the prescription.

[0159] Table 13, prescription composition of riociguat inhalation aerosol and orifice diameter / length characteristic parameters of inhalation device

[0160] Table 14, MMAD, GSD, FPF detection values corresponding to each prescription in Table 13

[0161] Example 7 Stability Investigation of Leo xijunba Aerosol Samples:

[0162] The Leo xijunba aerosol samples of prescription numbers: 3, 4, 5, 9, 13, 14, 15, 18, 19, 20, 24, 25, 29, 30, 34, 35, 39, 40, 42, 45, 46, 50, 51, 55, 56, 60, 61, 65, 67, 81, 82, 86, 87, 92, 93, 97, 98, 99 in Example 6 were stored at 25℃ / 60% RH and 40℃ / 75% RH, and the changes in impurity content and FPF detection value (the FPF detection value at 40℃ / 75% RH) were detected.

[0163] Table 15 Stability Investigation of Leo xijunba Aerosol Samples

[0164] Obviously, the above examples are merely illustrative and not limiting. Based on the above description, those skilled in the art can make other different forms of changes or variations. Here, it is not necessary and impossible to exhaust all the embodiments. The obvious changes or variations derived therefrom are still within the protection scope of the present application.

Claims

1. An inhalable pharmaceutical composition comprising a soluble guanylate cyclase receptor agonist, characterized in that, Comprise: an SGC receptor agonist or a pharmaceutically acceptable salt thereof; and at least one inhalable pharmaceutical excipient for aerosolization.

2. The inhalable pharmaceutical composition comprising a soluble guanylate cyclase receptor agonist according to claim 1, wherein, the dosage form of the pharmaceutical composition comprises an inhalation aerosol, an inhalation powder mist, an inhalation spray mist, an inhalation liquid formulation, an inhalation soft mist, or a formulation convertible to a vapor; preferably, a suspension-type inhalation aerosol.

3. The inhalable pharmaceutical composition comprising a soluble guanylate cyclase receptor agonist according to claim 1 or 2, wherein, the SGC receptor agonist or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is in the form of a particle or a solution; and / or, the inhalable pharmaceutical excipient comprises a surfactant, a propellant, a dispersant, and / or a suspending agent.

4. The inhalable pharmaceutical composition comprising a soluble guanylate cyclase receptor agonist according to claim 3, wherein, when the SGC receptor agonist or a pharmaceutically acceptable salt thereof is in the form of a particle, the particle size distribution D50 thereof ranges from 0.1 to 10 pm; preferably, the particle size distribution D50 thereof ranges from 0.1 to 5 pm.

5. The inhalable pharmaceutical composition comprising a soluble guanylate cyclase receptor agonist according to claim 4, wherein, the surfactant is selected from at least one of Tween 80, Tween 20, Span 20, Span 85, oleic acid, and phospholipid pharmaceutical excipients; preferably, the phospholipid pharmaceutical excipient comprises lecithin and / or distearoyl phosphatidylcholine; preferably, the surfactant is oleic acid; preferably, the content of the surfactant in the pharmaceutical composition ranges from 0 to 5% wt.

6. The inhalable pharmaceutical composition comprising a soluble guanylate cyclase receptor agonist according to any one of claims 3 to 5, wherein, the propellant is selected from at least one of HFA-134a, HFA-152a, tetrafluoroethane, HFA-227ea, heptafluoropropane, and HFO-1234ze; preferably, the propellant is HFA-134a; preferably, the content of the propellant in the pharmaceutical composition ranges from 50 to 99.9999% wt.

7. The inhalable pharmaceutical composition comprising a soluble guanylate cyclase receptor agonist according to any one of claims 3 to 6, wherein, the dispersant is selected from at least one of anhydrous ethanol, propylene glycol, polyethylene glycol, and water; preferably, the dispersant is anhydrous ethanol; preferably, the content of the dispersant in the pharmaceutical composition ranges from 0 to 30% wt.

8. The inhalable pharmaceutical composition comprising a soluble guanylate cyclase receptor agonist according to any one of claims 3 to 7, wherein, the suspending agent is selected from polyvinylpyrrolidones; preferably, the suspending agent is at least one of PVP (K25), PVP / 17PF, and PVP (K30); preferably, the content of the suspending agent in the pharmaceutical composition ranges from 0 to 5% wt.

9. The inhalable medicament composition comprising a soluble guanylate cyclase receptor agonist according to any one of claims 3-8, wherein, the SGC receptor agonist or a pharmaceutically acceptable salt thereof comprises at least one of riociguat, vericiguat, and patiromer; preferably, the SGC receptor agonist or a pharmaceutically acceptable salt thereof is riociguat.

10. The inhalable medicament composition comprising a soluble guanylate cyclase receptor agonist according to any one of claims 3-9, wherein, the SGC receptor agonist or a pharmaceutically acceptable salt thereof is present in the medicament composition in an amount ranging from 0.01 to 20% wt, the surfactant is present in an amount ranging from 0 to 5% wt, the propellant is present in an amount ranging from 50% to 99.9999% wt, the dispersant is present in an amount ranging from 0 to 30% wt, and the suspending agent is present in an amount ranging from 0 to 5% wt; alternatively, the SGC receptor agonist or a pharmaceutically acceptable salt thereof is present in the medicament composition in an amount ranging from 25 to 1000 μg per puff.

11. The inhalable medicament composition comprising a soluble guanylate cyclase receptor agonist according to any one of claims 3-10, wherein, the inhalation device for the medicament composition comprises a metering valve, a driver, an adapter, a nozzle, a canister, a counter, and other necessary components.

12. The inhalable medicament composition comprising a soluble guanylate cyclase receptor agonist according to claim 11, wherein, the spray orifice of the driver has a diameter ranging from 0.15 to 0.7 mm and a length ranging from 0.3 to 2 mm; preferably, the spray orifice of the driver has a diameter ranging from 0.3 to 0.4 mm and a length ranging from 0.6 to 1.0 mm.

13. The inhalable medicament composition comprising a soluble guanylate cyclase receptor agonist according to any one of claims 1-12, wherein, when the medicament composition is administered, the spray parameters thereof satisfy at least one of the following: (1) the plume angle is 15-60°; preferably, the plume angle is 20-40°; (2) the fine particle dose distribution FPF value is greater than 15%; preferably, the fine particle dose distribution FPF value is greater than 40%; (3) the aerodynamic mass median diameter of the aerosol particles ranges from 1 to 10 μm; preferably, from 1 to 5 μm.

14. The inhalable medicament composition comprising a soluble guanylate cyclase receptor agonist according to any one of claims 1-13, wherein, T max values of 5 min to 30 min; preferably, the preparation method of the inhalable medicament composition comprising a soluble guanylate cyclase receptor agonist is also included, which comprises: preparing a dosage form acceptable in the pharmaceutical field according to the formula.

15. Use of the inhalable medicament composition comprising a soluble guanylate cyclase receptor agonist according to any one of claims 1-14 in any one of the following: in the preparation of a medicament for preventing and treating pulmonary arterial hypertension of the first type; the pulmonary arterial hypertension of the first type comprises arterial pulmonary arterial hypertension PAH. Use in the manufacture of a medicament for the prevention and treatment of Group 4 pulmonary arterial hypertension; said Group 4 pulmonary arterial hypertension comprising chronic thromboembolic pulmonary arterial hypertension CTEPH; Use in the manufacture of a medicament for the prevention and treatment of Group 3 pulmonary arterial hypertension; said Group 3 pulmonary arterial hypertension comprising respiratory diseases causing pulmonary arterial hypertension diseases; said respiratory diseases causing pulmonary arterial hypertension diseases comprising chronic obstructive pulmonary disease causing pulmonary arterial hypertension PH-COPD; or, idiopathic interstitial pneumonia causing pulmonary arterial hypertension PH-ILD.

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