Inhalable pharmaceutical composition containing soluble guanylate cyclase receptor stimulant and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to an inhalable pharmaceutical composition containing a soluble guanylate cyclase (SGC) receptor stimulant and application of the inhalable pharmaceutical composition, and clinical adverse reactions of medicines can be remarkably reduced. According to the pharmaceutical composition, the administration dosage is reduced, on the premise that the drug effect is kept unchanged, the hypotension side effect caused in the administration process is reduced, and the normal blood pressure level is rapidly recovered after administration. The pharmaceutical composition provided by the invention needs to be combined with matched instruments for use, wherein the pharmaceutical composition comprises an SGC receptor stimulant drug and other inhalable pharmaceutic adjuvants. The lung deposition rate can reach more than 40% under the combination of a specific prescription and instruments. Through inhalation of the pharmaceutical composition, an SGC receptor stimulant can enter blood more quickly, and pharmacokinetic parameters such as Tmax are improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist and its use. Background Technology

[0002] Pulmonary hypertension (PH) is a disease caused by abnormally high pressure in the pulmonary arterial system. Unlike systemic hypertension, PH primarily affects the pulmonary arteries, but as the disease progresses, it also affects other pulmonary vessels such as pulmonary capillaries and pulmonary veins. Currently, there are clinically approved medications for PAH (WHO Group I), chronic thromboembolic pulmonary hypertension (CTEPH, WHO Group IV), and interstitial lung disease-related pulmonary hypertension (PH-ILD, WHO Group III). These drugs primarily target three major signaling pathways in the pathogenesis of pulmonary hypertension: prostacyclin, endothelin, and nitric oxide.

[0003] SGC receptor agonists belong to a class of drugs in the nitric oxide pathway. They specifically bind to and activate the oxidized, heme-free form of SGC, thereby promoting cGMP production. This is currently the only SGC receptor agonist drug approved for the treatment of pulmonary hypertension. The overall adverse reaction rate in the riociguat treatment group compared to the placebo group was: headache (27% vs 13%), dyspepsia / 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 drug is an oral tablet, currently available in five dosage strengths: 0.5mg, 1.0mg, 1.5mg, 2.0mg, and 2.5mg, with the oral dose increasing by 0.5mg every two weeks based on patient tolerance) are gastrointestinal discomfort and hypotension. The hypotension side effect is related to the systemic vasodilatory effect of oral riociguat. In fact, after oral administration of riociguat, the proportion of drug exposure in lung tissue is less than 2% of the total systemic drug exposure of riociguat (refer to the results of the tissue distribution study of oral riociguat in the PMDA review document).

[0004] Currently, the only commercially available riociguat original drug, Adempas, is in oral formulation, and there are no research reports on inhaled riociguat formulations. Based on the aforementioned clinical side effects of oral riociguat, this invention develops an inhaled riociguat drug that delivers the drug directly to the pulmonary blood vessels, reducing the drug's impact on other organs and minimizing gastrointestinal discomfort and hypotension during riociguat treatment of pulmonary hypertension. The relatively high drug concentration in the lungs allows it to maintain the same or better therapeutic effect as the oral original drug. Simultaneously, compared to oral medication, it can improve T... max Pharmacokinetic parameters are optimized to allow for faster drug absorption and efficacy, rapidly relieving symptoms in patients with pulmonary hypertension and improving treatment adherence. Summary of the Invention

[0005] Based on the current clinical application status of existing drugs for pulmonary arterial hypertension (PAH), and considering the side effects and deficiencies disclosed in the existing technology of riociguat, this invention focuses on developing an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist. This composition delivers the therapeutically effective SGC receptor agonist riociguat to the target organ (lung tissue) in a safe and effective aerosol formulation, while significantly reducing the severity and incidence of systemic side effects of SGC receptor agonists, such as hypotension and gastrointestinal discomfort. Furthermore, this invention, through direct delivery of riociguat to lung tissue, has been shown to achieve equivalent or better therapeutic effects compared to oral administration of less medication. As detailed below, oral SGC receptor agonists can significantly decrease systemic blood pressure indicators such as systolic blood pressure (SBP) and diastolic blood pressure (DBP), but lower pulmonary administration significantly improves the decrease in systemic blood pressure. This invention also unexpectedly discovered that pulmonary delivery of riociguat can significantly improve T... max Pharmacokinetic parameters.

[0006] Therefore, the present invention provides the following technical solution:

[0007] An inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, comprising:

[0008] SGC receptor agonists or pharmaceutically acceptable salts thereof; and

[0009] At least one excipient for inhalation that can be aerosolized.

[0010] Optionally, the dosage form of the pharmaceutical composition includes an inhaled aerosol, an inhaled powder, an inhaled spray, an inhaled liquid formulation, an inhaled soft fog, or a formulation that can be converted into vapor;

[0011] Preferably, it is a suspension-type inhalation aerosol.

[0012] Optionally, in the pharmaceutical composition, the SGC receptor agonist or a pharmaceutically acceptable salt thereof is present in particulate or solution form;

[0013] And / or, the inhaled pharmaceutical excipients include surfactants, propellants, dispersants and / or suspending agents.

[0014] Optionally, when the SGC receptor agonist or its pharmaceutically acceptable salt is present in particulate form, its particle size distribution D50 ranges from 0.1 to 10 μm.

[0015] Preferably, its particle size distribution D50 ranges from 0.1 to 5 μm.

[0016] Optionally, the surfactant is selected from at least one of Tween 80, Tween 20, Span 20, Span 85, oleic acid, and phospholipid pharmaceutical excipients;

[0017] Preferably, the phospholipid pharmaceutical excipients include lecithin and / or distearate phosphatidylcholine (DSPC);

[0018] Preferably, the surfactant is oleic acid;

[0019] Preferably, the content of the surfactant in the pharmaceutical composition ranges from 0 to 5% wt.

[0020] Optionally, the propellant is selected from at least one of HFA-134a, HFA-152a, tetrafluoroethane, HFA-227ea, heptafluoropropane and HFO-1234ze;

[0021] Preferably, the propellant is HFA-134a;

[0022] Preferably, the content of the propellant in the pharmaceutical composition ranges from 50 to 99.9999% wt.

[0023] Optionally, the dispersant is selected from at least one of anhydrous ethanol, propylene glycol, polyethylene glycol, and water;

[0024] Preferably, the dispersant is anhydrous ethanol;

[0025] Preferably, the content of the dispersant in the pharmaceutical composition ranges from 0 to 30% wt.

[0026] Optionally, the suspending agent is selected from polyvinylpyrrolidone (PVP) derivatives;

[0027] Preferably, the suspending agent is at least one of PVP (K25), PVP / 17PF, and PVP (K30);

[0028] Preferably, the content of the suspending agent in the pharmaceutical composition ranges from 0-5% wt.

[0029] Optionally, the SGC receptor agonist or a pharmaceutically acceptable salt thereof includes, but is not limited to, at least one of riociguat, veliciguat, and palicidal.

[0030] Preferably, the SGC receptor agonist or a pharmaceutically acceptable salt thereof is riociguat.

[0031] Optionally, in the pharmaceutical composition, the SGC receptor agonist or its pharmaceutically acceptable salt comprises 0.01-20% wt, the surfactant comprises 0-5% wt, the propellant comprises 50%-99.9999% wt, the dispersant comprises 0-30% wt, and the suspending agent comprises 0-5% wt; optionally, the propellant comprises 50%-99.99% wt.

[0032] Optionally, the SGC receptor agonist or a pharmaceutically acceptable salt thereof in the pharmaceutical composition ranges from 25 to 1000 μg / puff.

[0033] Optionally, the inhalation device for the drug composition may be an inhalation device comprising a variety of components including a metering valve, a actuator, an adapter, a nozzle, a canister, a metering counter, and other necessary parts.

[0034] Optionally, the nozzle diameter of the actuator ranges from 0.15 to 0.7 mm, and the nozzle length ranges from 0.3 to 2 mm.

[0035] Preferably, the nozzle diameter of the actuator is in the range of 0.3-0.4 mm, and the nozzle length is in the range of 0.6-1.0 mm.

[0036] Optionally, when the pharmaceutical composition is applied, its spray parameters satisfy at least one of the following:

[0037] (1) The plume angle is 15-60°; preferably, the plume angle is 20-40°;

[0038] (2) The fine particle dose distribution FPF value is greater than 15%; preferably, the fine particle dose distribution FPF value is greater than 40%;

[0039] (3) The aerodynamic mass median particle size (MMAD) of the aerosol particles ranges from 1 to 10 μm; preferably, it is 1 to 5 μm.

[0040] Optionally, when the pharmaceutical composition is administered, T max The value is 5 min to 30 min.

[0041] A method for preparing an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, comprising: preparing a dosage form acceptable in the pharmaceutical field according to a formulation.

[0042] Optionally, the dosage form includes inhaled aerosols, inhaled powders, inhaled sprays, inhaled liquid formulations, inhaled soft fogs, or formulations convertible to vapor; preferably, it is a suspension-type inhaled aerosol. Preferably, a prescribed amount of surfactant and / or suspending agent is dissolved in a dispersant, a prescribed amount of riociguat is added, the mixed dispersion is dispensed into aluminum cans, and a prescribed amount of propellant is filled through a valve installed on the can.

[0043] The use of the inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist in any of the following:

[0044] (1) Use in the preparation of medicines for the prevention and treatment of pulmonary hypertension of Group 1 (WHO Group 1); Group 1 pulmonary hypertension (WHO Group 1) includes arterial pulmonary hypertension (PAH);

[0045] (2) Use in the preparation of medicines for the prevention and treatment of pulmonary hypertension of Group 4 (WHO Group 4); said Group 4 includes chronic thromboembolic pulmonary hypertension (CTEPH);

[0046] (3) Use in the preparation of medicines for the prevention and treatment of pulmonary hypertension of Group 3 (WHO Group 3); wherein Group 3 pulmonary hypertension includes pulmonary hypertension caused by respiratory diseases; wherein pulmonary hypertension caused by respiratory diseases includes pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD); or pulmonary hypertension associated with interstitial lung disease (PH-ILD).

[0047] The technical solution of this invention has the following advantages:

[0048] 1. The present invention provides an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, comprising: an SGC receptor agonist or a pharmaceutically acceptable salt thereof; and at least one inhalation pharmaceutical excipient that can be aerosolized; on the one hand, the composition can deliver an SGC receptor agonist drug or a pharmaceutically acceptable salt thereof (such as riociguat) that can exert effective therapeutic effects to a target organ (lung tissue) in a safe and effective aerosol formulation. By directly delivering the riociguat drug to the lung tissue, it has been shown that it can achieve the same or better therapeutic effects with less drug compared to oral treatment;

[0049] On the other hand, the systemic side effects of SGC receptor agonists or their pharmaceutically acceptable salts, such as hypotension and gastrointestinal discomfort, can be reduced. Inhaled medications avoid contact with the gastrointestinal tract, thus resulting in a lower rate and significantly reduced incidence of gastrointestinal adverse reactions. Oral SGC receptor agonists can cause a significant decrease in systemic blood pressure indicators such as SBP and DBP, but lower pulmonary doses can significantly improve the decrease in systemic blood pressure.

[0050] The present invention also unexpectedly discovered that transpulmonary delivery of the riociguat pharmaceutical composition of the present invention significantly improves T... max Pharmacokinetic parameters: This drug composition, when inhaled, allows the SGC receptor agonist to enter the bloodstream more rapidly.

[0051] 2. The present invention provides an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, wherein the SGC receptor agonist or a pharmaceutically acceptable salt thereof is present in particulate or solution form; and / or, the inhalation excipients include surfactants, propellants, dispersants and / or suspending agents; the pharmaceutical composition provided by the present invention comprises an SGC receptor agonist drug and other inhalable pharmaceutical excipients, and under specific formulation combinations, the lung deposition rate can reach more than 40%, with high stability, high compatibility and higher FPF.

[0052] 3. This invention provides an inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, wherein the actuator has an orifice diameter ranging from 0.15 to 0.7 mm and an orifice length ranging from 0.3 to 2 mm; preferably, the actuator has an orifice diameter ranging from 0.3 to 0.4 mm and an orifice length ranging from 0.6 to 1.0 mm. When used with the aforementioned nebulizer, the pharmaceutical composition provided by this invention achieves a lung deposition rate of over 40% and exhibits high stability. Attached Figure Description

[0053] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0054] Figure 1 These are the pharmacokinetic curves of each group in Example 1 of this invention;

[0055] Figure 2 These are the SBP of SD rats in each group in Experiment Example 3 of this invention; the horizontal axis in the figure is in h (hours), and the vertical axis is in mmHg;

[0056] Figure 3 The figure shows the systolic blood pressure change ΔSBP of SD rats in each group in Experiment Example 3 of this invention; the horizontal axis is in h (hours) and the vertical axis is in mmHg.

[0057] Figure 4 The figures show the DBP of SD rats in each group in Experiment Example 3 of this invention; the horizontal axis is in h (hours) and the vertical axis is in mmHg.

[0058] Figure 5 The figure shows the diastolic blood pressure change ΔDBP of SD rats in each group in Experiment Example 3 of this invention; the horizontal axis is in h (hours) and the vertical axis is in mmHg.

[0059] Figure 6 The results are the detection results of right ventricular systolic pressure (RVSP), right ventricular function dp / dt(max), dp / dt(min), carotid artery blood pressure, and pulmonary aortic pressure (mPAP) of SD rats in each group in Experiment Example 4 of this invention.

[0060] Figure 7 These are microscopic photographs of HE-stained pathological sections of the right heart and lung tissues of SD rats in each group of Experiment Example 4 of this invention.

[0061] Figure 8 This is the comparative analysis result of the pulmonary arterial media thickness of SD rats in each group in Experiment Example 4 of this invention;

[0062] Figure 9 It is the spray form of prescription 1 in embodiment 5 of the present invention;

[0063] Figure 10 It is the spray form of prescription 2 in embodiment 5 of the present invention;

[0064] Figure 11 It is the spray form of prescription 3 in embodiment 5 of the present invention;

[0065] Figure 12 It is the spray form of prescription 4 in embodiment 5 of the present invention;

[0066] Figure 13 This refers to the spray form of prescription 5 in embodiment 5 of the present invention. Detailed Implementation

[0067] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0068] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0069] LeoCroat:

[0070] LeoCroat Riociguat is a first-in-class soluble guanylate cyclase agonist used to treat CTEPH (unresectable or persistent / recurrent postoperative pulmonary arterial hemorrhage) or PAH (see: Rare Disease Treatment Guidelines 2019). It has been designated an orphan drug by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA). It has positive effects on improving patient mobility, WHO functional classification, and pulmonary hemodynamic parameters; currently, most of its adverse reactions are attributed to its vasodilatory mechanism. However, due to its serious bleeding and fetal risks, riociguat is contraindicated in pregnant women.

[0071] The chemical structural formula of liosqua is as follows:

[0072]

[0073] CAS No.: 625115-55-1.

[0074] Riociguat has a molecular weight of 422.4 g / mol and is a white or pale yellow solid powder. Its solubility in water is 4 mg / L at 25°C, and its melting point is 247-251°C. Its solubility is significantly increased under low pH conditions.

[0075] SGC receptor agonists:

[0076] Since the discovery of nitric oxide (NO) in 1998 and the subsequent Nobel Prize, intensive basic research has led to a better understanding of NO's downstream targets. For example, the discovery that SGC receptor agonists can bind directly to SGC receptors independently of NO and trigger the production of cGMPs—a unique mechanism of action—led to the approval in 2013 of riociguat, the first SGC receptor agonist, for the treatment of various types of heart failure (PH). Following this, the SGC receptor agonist vericiguat was also shown in studies to limit cardiomyocyte hypertrophy, thereby reducing cardiac fibrosis. It demonstrated significant improvements in cardiac function in heart failure patients in multiple clinical trials and was therefore approved for the treatment of heart failure (HF) in 2022.

[0077] SGC receptor agonists act on the NO / cGMP signaling pathway to dilate blood vessels, a widely accepted mechanism of action. In some preclinical animal studies, the dose-dependent antihypertensive effect of SGC receptor agonists has been demonstrated, with particularly pronounced blood pressure reduction at higher doses. However, in some cases, hypotension may occur as a side effect. Given the prevalence of hypotension as a side effect of SGC receptor agonists in disease treatment, this invention provides an inhalable SGC receptor agonist-containing pharmaceutical composition that can alleviate hypotension to some extent, as described in the embodiments of this invention (an experiment monitoring blood pressure levels in SD rats under pulmonary administration versus oral administration conditions).

[0078] SGC (Soluble Guanylate Cycloyl Chloride):

[0079] Riocigua is a heterodimeric protein composed of α and β subunits, with the β subunit containing a heme group. NO binds to the heme group on the SGC, inducing a conformational change, activating the enzyme's catalytic domain, and promoting cGMP production. Riocigua is NO-independent and can directly bind to the α subunit of the SGC, enhancing the enzyme's catalytic activity and thus increasing cGMP production.

[0080] Inhalable compositions in aerosol form:

[0081] Inhalation therapy, a treatment method with a long history, can be traced back more than 2,000 years. Its rise is inseparable from modern pharmacological research on the respiratory system, such as airway structure, aerosol delivery, and deposition. Major discoveries in 19th-century asthma treatments (such as beta-agonists, corticosteroids, and anticholinergics) laid the foundation for the transition from early delivery systems using nebulizers (which convert liquid medications into fine aerosol particles for inhalation) to more advanced delivery systems. In 1956, 3M invented the now-common pressurized metered-dose inhaler (pMDI); in the late 1960s, Fisons Pharmaceuticals invented the Spinhaler, a lactose-carrier mixture and the precursor to the modern dry powder inhaler (DPI). The soft mist inhaler (SMI) emerged in the late 1980s; this delivery technology produces extremely fine aerosols but is not particularly suitable for medications requiring precise dosing and low flow rates. Each of these four aerosol inhalation methods has its own advantages and disadvantages. However, judging from the historical evolution of aerosol drug delivery technology over the past half-century, small and portable aerosol generators may be more in line with the needs of the times.

[0082] In addition, the feasibility of drug delivery technology, dosage limitations, and user requirements at the patient level need to be considered, taking into account the physicochemical properties of the drug. Both pMDI and DPI are small, portable inhalers that can deliver extremely small amounts of medication to the lungs, such as... (Budesonide / formoterol inhaler) delivers a micro-dose of 80 μg per actuation. Combined with the low-dose efficacy of highly active drugs like riociguat and pulmonary administration, both pMDI and DPI technologies provide accurate and micro-volume delivery to the lungs, exhibiting certain drug-like properties. However, DPI requires sufficient inspiratory flow, which may be ineffective for some patients (such as children or the elderly), and for patients with pulmonary hypertension whose respiratory function is impaired. pMDI, on the other hand, utilizes its own propellant system to deliver the drug to the lungs, reducing reliance on the patient's own inspiratory flow.

[0083] This invention provides pharmaceutical compositions containing riociguat suitable for inhalation administration, wherein the 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 formulations encapsulating riociguat in a matrix of liposomes or other materials. Considering the above-described practical situation, in the following embodiments, this invention preferably utilizes pMDI technology to deliver the riociguat-containing pharmaceutical composition.

[0084] pMDI formulation technology

[0085] Since the advent of pMDI (push-metered inhaler) formulation technology in the mid-1950s, it has become the most widely used route of administration for patients with asthma and COPD (chronic obstructive pulmonary disease). Compared with oral administration, pMDI inhalation has the advantages of rapid onset of action and a low incidence of systemic side effects. Although most marketed pMDI products are bronchodilators and steroids, they have also provided valuable technical insights for improving the administration methods of drugs for treating local lesions, especially lung diseases.

[0086] pMDI formulations primarily rely on the propulsion system to expel the drug formulation from the device in a form that can be inhaled orally by the patient. The propellant is typically composed of HFA (liquefied hydrofluorocarbons), selected to provide the required vapor pressure and stability for the formulation. Currently, pMDI formulations generally include: the active pharmaceutical ingredient, one or more propellants, and other optional pharmaceutical excipients such as solubilizers, surfactants, suspending agents, and lubricants. The active pharmaceutical ingredient in the pMDI device is generally present in a fully dissolved or particulate suspension form within the liquefied propellant system. However, most active pharmaceutical ingredients are not sufficiently soluble in the propellant, and even with the addition of solubilizers such as ethanol, they cannot be fully dissolved in the formulation. The MMAD (macroscopic diameter distribution) of the droplets sprayed by pMDI aerosols must be strictly controlled to be less than 10 μm to ensure drug delivery to the lungs. Controlling the MMAD parameter of solution-type aerosol formulations is more difficult than controlling particulate suspension formulations (the solvent evaporation rate affects the droplet size), therefore, formulations with drug particles suspended in the propellant are more preferred.

[0087] Ethanol:

[0088] In solution-type pMDI formulations, ethanol is added as a co-solvent to promote the dissolution of the active pharmaceutical ingredient. In particulate suspension aerosol formulations, ethanol can be used to dissolve pharmaceutical excipients such as surfactants and suspending agents, and also lubricates valves and canisters to prevent drug particle adhesion. Some studies have also shown that adding appropriate concentrations of co-solvent excipients such as ethanol to particulate suspension systems can reduce flocculation and precipitation in the suspension system. Besides ethanol, other co-solvents that can be used in pMDI formulations include other alcohols, ethers, and polyethylene glycol organic solvents. For example, some studies have shown that by appropriately selecting and adding co-solvents, such as ethanol, to aerosol propellant systems, flash evaporation of the propellant at the nozzle can be suppressed, thereby preventing direct drug deposition at the nozzle and reducing the potential risk of nozzle clogging.

[0089] Surfactants:

[0090] Adding traditional surfactants, such as oleic acid, Tween 80, and PEG1000, to the formulation of some pMDI preparations can reduce the adhesion between drug particles and minimize the occurrence of drug particle agglomeration.

[0091] Suspension agents:

[0092] Vinyl polymers, especially pharmaceutical excipients PVP, are often used in suspensions to prolong the suspension and dispersion time of drug particles. They are also used to maintain the FPF (float-free powder) of pMDI formulations during storage without significant changes.

[0093] MMAD (Mass Median Aerodynamic Diameter):

[0094] MMAD (Medium-to-Density Aspect Ratio) refers to the percentage of particles in an aerosol whose mass is greater than or equal to its diameter (50%). Measuring MMAD is crucial for assessing aerosol sedimentation behavior and the effectiveness of pulmonary drug delivery, as different particle sizes affect particle deposition sites in the respiratory tract. Generally, particles with a diameter between 1 and 5 micrometers are best suited for pulmonary drug delivery.

[0095] FPF (Fine Particle Fraction):

[0096] FPF (Fluorescent Particle Flow Rate) refers to the percentage by mass of particles smaller than a specific diameter (typically 5 micrometers or less) in an aerosol. Measuring FPF is crucial for determining the drug delivery efficiency of inhaled formulations, as a higher FPF value generally indicates better drug delivery to the lungs. GSD (Geometric Standard Deviation):

[0097] GSD is a statistical parameter used to describe the size distribution of aerosol particles. It measures the variability of particle diameter, particularly on a logarithmic scale. In drug delivery systems, GSD is an important parameter because it affects drug deposition behavior and bioavailability in the respiratory tract. Generally, a smaller GSD value (e.g., 1.5 to 2.0) is considered ideal because it indicates a narrower particle size distribution, which helps improve drug delivery efficiency.

[0098] The following is a formula showing the correlation between various parameters in a pMDI formulation:

[0099] C p =6C D exp(4.5ln 2 (GSD) / ρΠ(MMD)^3;

[0100] in:

[0101] Cp Concentration of suspended drug particles in the formulation (per milliliter of particles);

[0102] C D The mass concentration of drug particles in the formulation (in grams per milliliter);

[0103] ρ: Particle density (in grams per milliliter);

[0104] MMD: Median diameter of the mass of the micronized drug suspended in the formulation;

[0105] GSD: Geometric standard deviation (dimensionless) of micronized drug suspended in the formulation.

[0106] pMDI inhalation device.

[0107] A complete pMDI dosage form consists of two parts: the prescription and the drug delivery system. The drug delivery system comprises three parts: a pressure-resistant container, a metering valve system, and a driver. The drug delivery system, i.e., the pMDI inhalation device, is a key component of the pMDI dosage form and is crucial to the drug's performance in in vitro deposition prediction experiments (ACI and NGI experiments). It also directly affects the amount of drug deposited in the lungs and respiratory tract to exert its therapeutic effect. The drug delivery system also needs to be tailored to the pathological characteristics of the drug's target indication (systemic drug therapy absorbed into the bloodstream via the alveoli, or a specific lesion site such as the upper respiratory tract, lower respiratory tract, respiratory terminal area, or alveoli) to create differentiated spray patterns and particle size distribution characteristics, and to reduce overall drug deposition in the oral cavity and pharynx. According to relevant literature, pMDI drug delivery systems can currently be broadly classified into three types based on the driver's working principle: 1. 'Press and Breath' type drivers; 2. 'Mechanical Break-up' type drivers; and 3. 'Breath-Triggered' type drivers. Depending on the driver principle and component design, the main types of devices currently on the market are: Modulite B 30 (Chiesi), SkyeFine™ and SkyeDry™ (SkyePharma) inhalation devices.

[0108] The formulation of the invention is filled into a container capable of withstanding the vapor pressure of the HFA propellant, such as a plastic or plastic-coated glass bottle, or more preferably a metal canister. Metal canisters specifically include stainless steel canisters and aluminum canisters with anodized or organic coatings. The volume of the metering valve used in the invention is designed according to the dosage of each injection. Valve gaskets are made of any suitable elastic material that prevents propellant leakage, such as low-density polyethylene and rubber. Valve seals, including gasket seals and seals around the metering chamber, are preferably made of inert materials that do not degrade with the formulation of the invention. Suitable canisters, metering valves, valve gaskets, valve seals, valve stems, and other components of the invention can also be purchased from aerosol device manufacturers. The material composition of the selected inhalation device meets the requirements of chemical, physical, and mechanical stability with the prepared inhalable composition.

[0109] According to existing technical references, changing the driver nozzle parameters affects key quality parameters of pMDI, such as plume angle, plume velocity, and plume duration, and further influences changes in drug deposition quality properties in the lungs, such as higher FPF and lower drug deposition in the pharynx. Existing literature indicates that the orifice length of commercially available suspension MDI products typically varies from 0.5 to 1.5 mm, while the orifice diameter is generally greater than 0.3 mm. The aforementioned prior art does not imply that riociguat suspension inhalation aerosol formulations can effectively deliver drugs via pMDI technology using the aforementioned conventional or non-conventional size parameters.

[0110] As used in this article, T max The value represents the time to peak blood concentration, which is the time required for a drug to reach its maximum blood concentration after entering the body.

[0111] As used in this article, C max (ng / h) represents the concentration value at which a drug reaches its maximum concentration in the human body. It is an important pharmacokinetic parameter that reflects the absorption of the drug in the human body.

[0112] As used in this article, D10 means that 10% of the particles have a diameter less than or equal to this value, D50 means that 50% of the particles have a diameter less than or equal to this value, and D90 means that 90% of the particles have a diameter less than or equal to this value.

[0113] As used in this article, HFA-134a, HFA-152a, tetrafluoroethane, HFA-227ea, heptafluoropropane and HFO-1234ze are all commercially available products.

[0114] As used in this article, PVP(K25), PVP / 17PF and PVP(K30) are all commercially available products.

[0115] As used in this article, a press indicates the dosage, and one press indicates the dosage of one press of the spray device.

[0116] Experimental Example 1: Pharmacokinetic Experiment of Pulmonary Administration vs. Oral Administration

[0117] Twenty-four SD rats (weighing 240-260g, approximately 10 weeks old) were purchased and divided into eight groups of three. After one week of acclimatization, SD rats in groups 1, 2, and 3 were administered riociguat solution (concentrations of 0.3mg / ml, 0.2mg / ml, and 0.1mg / ml, respectively, in physiological saline containing 10% wt ethanol) via pulmonary administration using a Microsprayer spray device (purchased from Shanghai Yuyan Scientific Instruments Co., Ltd.). The dosages (riociguat dosage) were 0.24mg / kg, 0.16mg / kg, and 0.08mg / kg, respectively, administered once. "Dosage" refers to the amount of riociguat drug, calculated based on the rat's body weight (kg). The dosage of riociguat was determined, and the dosing volume was determined based on the concentration of the solution (e.g., 0.3 mg / ml, 0.2 mg / ml, 0.1 mg / ml, etc.). The same administration method was used on SD rats in groups 4, 5, 6, and 7. For the riociguat suspension samples (25 mg and 15 mg of riociguat micropowder from Table 6, item 5 in Example 1, accurately weighed and added to 10 mL of dispersion matrix (a physiological saline solution containing Tween 80 (mass concentration of 0.05%)), the suspensions were thoroughly dispersed and mixed to prepare suspensions with concentrations of 2.5 mg / mL and 1.5 mg / mL, respectively. Different volumes of the drug solution were then drawn from the suspension for pulmonary administration according to the dosage. Lung administration (using a Microsprayer spray device) was performed at the following doses (Riociguat dosage): 0.5 mg / kg, 1 mg / kg, 2 mg / kg, and 4 mg / kg, administered once. For SD rats in group 8, a dispersion of riociguat original tablets was prepared by grinding the original tablets into powder (using the pulverization process described in Example 1, item 5). The powdered original tablets were then thoroughly dispersed and suspended in physiological saline to prepare suspensions of riociguat concentrations of 2.5 mg / mL and 5 mg / mL (the dosage volume was calculated based on rat weight and dosage). Oral administration was then performed at a dose (riociguat dosage) of 10 mg / kg, administered once. Blood samples were collected from SD rats in each group at 0.1 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 7 h, and 24 h after administration. The blood samples were centrifuged, and the supernatant was collected for drug content analysis. See the table below. Figure 1 The image shows the pharmacokinetic parameters obtained after LC-MS analysis of blood samples. From this, we can conclude that the oral riociguat drug T... maxThe value is 30 min, while the inhalation administration T max The value ranges from 5 to 30 minutes, indicating that inhalation administration has a more rapid onset of action. This further demonstrates that the micronized riociguat active pharmaceutical ingredient of a specific particle size provided by this invention, after being delivered to the lungs via a lung drug delivery device, exhibits good dissolution and absorption of the drug particles deposited in the lung tissue, directly reflecting the T-cell absorption into the bloodstream after pulmonary absorption. max Regarding parameters; furthermore, the riociguat active pharmaceutical ingredient with a specific particle size provided by this invention, through an aerosol propellant system, forms an aerosol containing drug particles, which, when inhaled orally into the lungs, can achieve a similar absorption into the bloodstream, and is directly reflected in T... max Regarding the parameters.

[0118] Table 1. Pharmacokinetic parameters of each group

[0119]

[0120] Experiment Example 2: Experiment comparing lung deposition rate via Microsprayer device drug delivery versus minimally invasive tracheal drug delivery

[0121] Referring to the drug administration of SD rats in group 7 of Experiment 1, the drug was administered via the trachea through the larynx using a Microsprayer device at a dose of 4 mg / kg. Fifteen minutes after administration, the SD rats were anesthetized and dissected. A large amount of drug particles were found deposited in the larynx and trachea. The larynx was then removed, and the lung tissue below the trachea was collected. The lung tissue weight (mg) was accurately measured. The lung tissue was homogenized using a homogenate solution (preparation method: add 2.5 mL of 17% H3PO4 and 2 g of ascorbic acid to 100 mL of 50% acetonitrile (containing 0.1% formic acid) and mix thoroughly). The drug content in the homogenate was analyzed using LC-MS. The theoretical drug deposition rate in the lungs after administration was calculated as: (Lung tissue riociguat drug content ÷ Total riociguat administered) × 100%. Further, a minimally invasive tracheal incision method was used on SD rats. Drug was administered through the tracheal incision site, via the tracheal-lung junction, and the theoretical drug deposition rate in the lungs was calculated using the same method as above. The table below shows the theoretical drug deposition rates in the lungs for the two pulmonary administration methods. It can be concluded that using the Microsprayer device via the trachea allows approximately 40% of the drug particles in the suspension prepared in this invention to be deposited in the lung tissue; using minimally invasive tracheal surgery via the tracheal-lung junction allows approximately 100% of the drug particles in the suspension provided in this invention to be deposited in the lungs. The latter administration method offers more precise dosage calculation and fewer external interference factors. Therefore, this administration method was prioritized in Experiment Example 3: the riociguat toxicology experiment of this invention. However, in Experiment Example 4, the pharmacodynamic experiment required continuous administration for 14 days. Continuous tracheal incision would cause greater trauma to the experimental animals, so the former administration method was prioritized in Experiment Example 4.

[0122] Table 2 shows the theoretical drug deposition rate in the lungs for the two pulmonary administration methods.

[0123]

[0124] Experiment Example 3: Leocida Toxicology Experiment

[0125] The experimental procedure included: administration of medication via nebulizer through the tracheal inlet after minimally invasive tracheal surgery, followed by blood pressure measurement of SD rats using a Softron BP-2010A smart non-invasive blood pressure monitor. SBP and DBP values ​​were recorded at 0h, 0.5h, 1.5h, 4h, and 24h for rats in each group: oral reference formulation (10mg / kg), nebulized administration (1.5mg / kg and 4mg / kg), and nebulized administration of blank solvent. Blood pressure changes in SD rats under nebulized and oral administration conditions were compared. The animal experimental groupings and medication administration details are as follows:

[0126] 1) The oral administration dose was 10 mg / kg, and the administration sample was a dispersion prepared from 2.5 mg riociguat original drug tablets (same as in Experiment 1); 5 SD mice (weight 240-260 g, age about 10 weeks) were used.

[0127] 2) Lung administration doses of 1.5 mg / kg and 4 mg / kg were administered. The samples were prepared riociguat suspensions (the blank solvent was a physiological saline solution containing 0.05% wt Tween 80, and the riociguat granules were prepared according to implementation scheme number 5 in Example 1. The riociguat granules were dispersed in the blank solvent to prepare suspensions with riociguat concentrations of 2.5 mg / mL and 5 mg / mL (the administration volume was calculated based on the rat weight and dosage); 5 SD rats (specific weight 240-260g, age 10 weeks) were used.

[0128] 3) The lung administration blank group consisted of the same volume of solvent as in 2) (containing 0.05% wt Tween 80 saline solution); 5 SD mice (weight 240-260g, age 10 weeks)

[0129] like Figures 2-5 The figures show the blood pressure monitoring of SBP and DBP in SD rats within 24 hours after oral administration of 10 mg / kg, pulmonary administration of 1.5 mg / kg, 4 mg / kg, and blank solvent administration. This indicates that pulmonary administration effectively reduces the risk of hypotension during riociguat treatment and rapidly restores normal blood pressure levels; compared with oral formulations of the same efficacy, inhaled administration significantly reduces blood pressure at C... max ΔSBP (systolic blood pressure SBP change / decrease) can decrease by 15%-100% in C max The ΔDBP (diastolic blood pressure DBP variable / reduction) can decrease by 15%-100%, indicating a rapid recovery of blood pressure after inhaled administration. max The time period is the same as the lung administration time in Experiment Example 1. max The value is 5min to 30min, which can correspond to Figures 2-5 The horizontal axis is 5 min to 30 min.

[0130] Furthermore, the mechanism of action of the suspension-type inhaled aerosol is as follows: the propellant, as part of the other raw and auxiliary materials of the powered nebulization suspension-type inhaled aerosol, forms an aerosol (nebulized particles). After the aerosol transports the drug particles into the lung tissue, the drug particles are deposited and dissolved in the lungs and absorbed by the lung tissue. Based on the above mechanism, this experiment used a minimally invasive tracheal inhalation method commonly used in animal studies of inhaled formulations, to administer the drug into the lungs via tracheal inhalation for toxicological testing. To ensure that the pulmonary absorption mechanism is the same as that of the suspension-type inhaled aerosol of this invention, the drug particle morphology in the drug sample of this experiment was set to be the same as that of the suspension-type inhaled aerosol of this invention. This ensures that the pharmacological and toxicological test can be used to verify the rationality of the pulmonary absorption of the suspension-type inhaled aerosol of this invention. From this experimental example, it can be concluded that blood pressure can be completely restored within 24 hours after inhalation of the suspension-type inhaled aerosol provided by this invention, while hypotension symptoms still exist 24 hours after oral administration.

[0131] Experiment Example 4: Pharmacodynamic Experiment of Leocidgua

[0132] Sixteen SD rats (240-260g, 10 weeks old) successfully induced a pulmonary hypertension model by subcutaneous injection of lily alkaloid (60mg / kg). These rats were then randomly divided into three groups: the G1 model group (n=4+2), the G2 drug-treated group (n=4+2), and the G3 positive control group (n=4).

[0133] The G1 (or G1-Vehicle) group received 100 μL of blank solvent (containing physiological saline solution with a mass concentration of 0.05% wt Tween 80) via the lungs through the Microsprayer device.

[0134] Group G2 (or G-BAY 63-2521) was administered 100 μL of a dispersion containing riociguat drug particles via a Microsprayer device at a dose of 4 mg / kg. The blank solvent was a physiological saline solution containing 0.05% wt Tween 80. The riociguat micropowder was prepared according to implementation scheme number 5 in Example 1. Suspensions with riociguat mass concentrations of 2.5 mg / mL and 5 mg / mL were prepared by dispersing the riociguat micropowder in the blank solvent (the administration volume was calculated based on the rat's body weight and the dose).

[0135] The G3 group (or G3-positive drug) was administered 10 mg / kg via gavage with a dispersion prepared from 2.5 mg riociguat original tablets (same as in Experiment 1).

[0136] After 14 days of continuous treatment with the above-mentioned groups, rats were anesthetized and right heart catheters were inserted to detect: RVSP, right ventricular function dp / dt(max), dp / dt(min), common carotid artery blood pressure, and mPAP. Lung and right heart tissue samples were collected from the dissected rats for pathological analysis, and the endothelial-media thickness of the pulmonary arterioles was compared among the groups. The specific experimental groups and drug administration details are shown in the table below:

[0137] (Note: Referring to the theoretical difference in lung deposition rate between microsprayer device-based pulmonary administration and tracheal minimally invasive administration in Experiment Example 2, the pulmonary administration dose of 4 mg / kg in Group G2 in this experiment is basically the same as the pulmonary administration dose of 1.5 mg / kg in Experiment Example 3.)

[0138] Table 3. Experimental Groups and Drug Administration

[0139]

[0140] The results of RVSP, right ventricular function dp / dt(max), dp / dt(min), carotid artery blood pressure, and mPAP index in rats of groups G1, G2, and G3 are as follows: Figure 6 As shown in the figure, the mPAP in the oral (10 mg / kg / day) group (G3) decreased from 30.06 mmHg to 31.37 mmHg compared to the pathological model group (G1), while the mPAP in the pulmonary administration group (4 mg / kg / day) (G2) decreased to 26.5 mmHg. The average RVSP in the oral (10 mg / kg / day) treatment group decreased from 28.47 mmHg to 18.65 mmHg compared to the pathological model group, and decreased to 21.38 mmHg in the pulmonary administration group (4 mg / kg / day).

[0141] Microscopic images of HE-stained pathological sections of right heart and lung tissue from rats in groups G1, G2, and G3 are shown below. Figure 7 As shown in the figure, the right ventricular cardiomyocytes of the rats in the pathological model group were hypertrophied and disordered, while the right ventricular cardiomyocytes in the pulmonary administration group / oral administration group were relatively neatly arranged, relatively uniform in size, and relatively evenly distributed. The pulmonary arterioles of the rats in the pathological model group had obvious stenosis, and the smooth muscle had obvious hyperplasia and hypertrophy. The pathological lesions of the pulmonary arterioles were reduced after pulmonary administration and oral administration.

[0142] The comparative analysis results of pulmonary arterial medial thickness in rats of groups G1, G2, and G3 are as follows: Figure 8As shown in the figure, the average media 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 to 9.44 μm in the pulmonary administration group (4 mg / kg / day) (p < 0.001).

[0143] Furthermore, the mechanism of action of the suspension-type inhaled aerosol is as follows: the propellant, as part of the other raw materials and excipients in the powered nebulization suspension-type inhaled aerosol, forms an aerosol (nebulized particles). After the aerosol transports the drug particles into the lung tissue, the drug particles are deposited and dissolved in the lungs and absorbed by the lung tissue. Based on the above mechanism, this experiment used the Microsprayer lung delivery device, commonly used in animal studies of inhaled formulations, to administer the drug for toxicology testing. To ensure that the lung absorption mechanism is the same as that of the suspension-type inhaled aerosol of this invention, the drug particle morphology in the drug-treated samples in this experiment was set to be the same as that of the suspension-type inhaled aerosol of this invention. This ensures that the efficacy test can be used to verify the rationality of the lung absorption of the suspension-type inhaled aerosol of this invention. Therefore, this experimental example shows that inhaling the suspension-type inhaled aerosol provided by this invention can treat pulmonary hypertension.

[0144] Experimental Example 5: Screening of Leocidgua Inhalation Formulations

[0145] 1. Solution-type nebulized inhalation liquid formulation

[0146] One embodiment of the present invention is the preparation of a solution-type riociguat nebulized inhalation liquid formulation. In this embodiment, a riociguat solution formulation with a dosage strength of 0.2 mg / mL is prepared, the pH of the solution system is controlled at 4 and 7, and a certain amount of solubilizing excipients is added to investigate the feasibility of preparing a riociguat solution formulation. Formulation preparation method:

[0147] Accurately weigh 0.2 g of riociguat raw material into a 1000 mL volumetric flask to prepare a riociguat solution with a theoretical concentration of 0.2 mg / mL. Control the following variables affecting the solution preparation: pH value of 4 or 7; addition or omission of a certain amount of solubilizing surfactants / pharmaceutical excipients; and different amounts of solubilizing surfactants / pharmaceutical excipients. The specific formulation design is shown in the table below for the formulation of a riociguat solution with a theoretical concentration of 0.2 mg / mL:

[0148] Table 4. Formula for Riociguat Solution

[0149]

[0150] This implementation plan aims to prepare a 0.2 mg / mL riociguat solution. Referring to the FDA review documents for riociguat, its solubility in aqueous solution at 25°C is 4 mg / L. Therefore, it is difficult to prepare a 0.2 mg / mL riociguat solution under aqueous solution conditions. Subsequently, the pH of the aqueous solution was adjusted to 4 in this implementation plan. Commonly used solubilizing surfactants for inhalation formulations (refer to the FDA website's DMF list of inhalation excipients), such as oleic acid, Tween 80, Tween 20, and polyethylene glycol, were added to the aqueous solution, but a 0.2 mg / mL riociguat solution could not be obtained. This indicates that due to the inherent solubility limitations of riociguat, it is difficult to prepare a solution formulation for nebulized inhalation.

[0151] 2. Solution-type inhaled aerosol

[0152] In one embodiment of the invention, the active ingredient of riocigua is fully dissolved in an ethanol organic solvent to form a solution. Other pharmaceutical excipients, such as surfactants, are added to the solution. The final prepared solution is then filled into an aerosol can equipped with a metering valve. A propellant, such as HFA134a, is then added to the can through the metering valve to prepare a solution-type inhalation aerosol. In this embodiment, a 100 μl volume valve is used to prepare the solution-type inhalation aerosol, with a proposed theoretical drug concentration of 200 μg / puff. This requires the drug to have a solubility greater than 2 mg / mL in the propellant system. Referring to the riocigua FDA product information, the solubility in ethanol is 800 mg / L, while the riocigua active pharmaceutical ingredient is insoluble in the propellant. If the ethanol mass percentage in the propellant system reaches 30%, a concentration of 24 μg / puff can be achieved, with 5 puffs required for efficacy. However, a 30% ethanol concentration has pulmonary toxicity and is therefore not feasible. When the ethanol content was reduced to 15%, each actuation was 12 μg, but ethanol still caused pulmonary toxicity. At a 10% ethanol content, pulmonary toxicity was milder, but a dose of 8 μg / amplitude was insufficient to achieve a therapeutic effect. In this implementation plan, the survival rate and physiological status of SD rats were investigated during pulmonary administration of solutions with different ethanol mass percentages. The following table shows the experimental results after 20 SD rats were randomly divided into 4 groups (5 rats / group):

[0153] Table 5. Survival rate and physiological status of SD rats after administration of solutions with different ethanol mass percentages to the lungs.

[0154]

[0155] From the above, it can be concluded that neither solution-type nebulized liquid formulations nor solution-type inhaled aerosols are suitable for use in riociguat drug inhalation formulations.

[0156] Example 1: Control of Active Pharmaceutical Ingredient Particle Size

[0157] Due to the inherent solubility limitations of riociguat active pharmaceutical ingredient (see the exploratory study in Example 5), it is difficult to develop it into a solution-based inhalation formulation. Therefore, it is preferable to prepare riociguat into drug particles of a specific size and surface morphology, and then aerosolize these particles for inhalation into the lungs via the mouth and nose to exert its therapeutic effect. In the treatment of pulmonary hypertension, the deposition of drug-containing aerosols at the correct target lesion sites in the respiratory system is of great significance for maximizing therapeutic efficacy and minimizing side effects. Generally, the smooth muscle cells of the pulmonary arteries and arterioles, and vascular endothelial cells in lung tissue are ideal therapeutic targets for pulmonary hypertension. The particle size distribution of the active pharmaceutical ingredient plays a crucial role in the ideal deposition of particles in the aerosol in the lungs.

[0158] One technical solution for controlling the particle size of the active pharmaceutical ingredient (API) in this invention involves dissolving riociguat in an organic solvent, or further adding a certain amount of amino acid-based pharmaceutical excipients such as leucine, glycine, and aspartic acid; sugar-based pharmaceutical excipients such as trehalose and mannitol; PVP and carboxymethyl starch, etc., to the organic solvent. The prepared drug-containing solution is then processed using a spray drying device, where nitrogen gas atomizes the solution into droplets, which are then rapidly evaporated in hot air to remove moisture from the droplets, resulting in dried drug particles. During the spray drying process, parameters such as feed rate, airflow velocity, and temperature are adjusted to control the particle size distribution of the final drug particles. These preparation processes can produce amorphous drug-containing particles, improving their solubility, especially for poorly soluble drugs like riociguat, thereby improving their bioavailability or enhancing the dissolution and release behavior of the drug after inhalation, thus increasing drug utilization in lung tissue.

[0159] One technical solution for controlling the particle size of the active pharmaceutical ingredient (API) in this invention is to use an air jet mill to pulverize the riocigua API. By controlling pulverization parameters such as inlet pressure, pulverization pressure, and feed rate, API micropowder with the desired particle size can be obtained. The table below shows the air jet milling test conditions and particle size results of the riocigua micropowder prepared in the laboratory:

[0160] Table 6. Airflow milling test conditions and particle size results of Riociguat micron powder

[0161]

[0162] The table shows that the particle size D50 of the active pharmaceutical ingredient (API) after air jet milling is less than 5 μm, which meets the requirements for preparing multiple batches of suspension-type riociguat aerosol samples. However, the embodiments in this invention are not limited to using API micropowder with a D50 of less than 5 μm as listed in the table above. Some embodiments also include selecting APIs with a D50 value of less than 7 μm or less than 10 μm to prepare samples. Finally, the particle size distribution requirement of the API substantially protected by this invention is limited to 0.1 μm < D50 < 10 μm, based on whether the fine particle drug dose ratio (FPF) value per actuation of the aerosol samples prepared from APIs with different particle size distributions meets the FPF limit in the national pharmacopoeia standard.

[0163] Example 2: Preparation of Riociguat suspension-type inhalation aerosol

[0164] One embodiment of the present invention is the preparation of riociguat inhalation aerosol. In this embodiment, riociguat raw material granules are prepared according to embodiment number 5 in embodiment 1. The riociguat raw material granules and the propellant are placed in a premixing tank and thoroughly mixed by high-speed stirring. The mixed drug is then pressed into an aerosol device through an overpressure filling device to prepare the riociguat inhalation aerosol. In the preparation process of the aerosol sample in this embodiment, according to different formulation design requirements, such as drug content per actuation, different types and amounts of surfactants, dispersant amounts, and types and amounts of suspending agents, the materials are added according to different mass ratios of each component to prepare corresponding formulations. These formulations are then filled into inhalation devices with different spray orifice diameter / shortage parameters. Referring to the requirements of the General Chapter 0951 of the 2020 edition of the Chinese Pharmacopoeia (Volume IV) for the determination of aerodynamic characteristics of fine particles in inhaled preparations, the aerodynamic particle size distribution of the prepared riociguat inhalation aerosol samples was evaluated using the Anderson Cascade Settling Chamber (ACI) device to assess whether the prepared aerosol samples met the expected lung deposition characteristics.

[0165] Formulation process:

[0166] The prescribed amount of surfactant and suspending agent pharmaceutical excipients were dissolved in the dispersant. After thorough stirring and dissolution, the prescribed amount of riociguat drug granules (granules numbered 5 in Table 6 of Example 1) was added. The stirring speed was controlled at 4000 rpm and the stirring time was 5 min. The thoroughly mixed dispersion was dispensed into aluminum cans, and the prescribed amount of propellant selected from HFA-134a was filled in through the valve installed on the can. 100 bottles of riociguat suspension-type inhalation aerosol with theoretical drug dosages of 100 μg / puff and 200 μg / puff were prepared (in actual preparation, 25% of the raw material needs to be overfilled to achieve the rated drug dosage per puff). The table below shows the prescription composition and nozzle diameter / length characteristic parameters of the inhalation device for a batch of 100 bottles of riociguat inhalation aerosol prepared according to the above method:

[0167] Table 7. Formulation composition of Riociguat inhaler and characteristic parameters of nozzle diameter / length of inhalation device

[0168]

[0169] Experimental procedure for detecting fine particle dosage using ACI equipment:

[0170] After ensuring the Anderson Classification Accumulator (ACI) is clean, conduct the experiment by connecting the prepared riociguat aerosol to the throat of the ACI via the interface. Set the detection flow rate (typically 28.3 L / min) and spray the aerosol five times to ensure sufficient sample is collected for analysis within the ACI. Thoroughly clean the collection port, throat, each stage of the deposition plate, and the filter test components with 50 mL of methanol. Analyze the collected samples using high-performance liquid chromatography (HPLC) to determine the amount of drug deposited on each test component. Import the drug deposit amount (in μg / bunch) from each test component into the analysis software program, which outputs the aerodynamic particle size distribution parameters such as MMAD, geometrical standard deviation (GSD), and FPF. The table below shows the drug deposit amounts of riociguat aerosol samples (formula numbers 1-5) in each component of the ACI:

[0171] Table 8. Drug deposition amount of liociguat aerosol samples in various components of the ACI device

[0172]

[0173]

[0174] The table below shows the MMAD, GSD, and FPF values ​​output by the analysis software after importing the drug content detection values ​​of each component in the ACI experiment for prescriptions 1-5. According to the Chinese Pharmacopoeia's method for determining the aerodynamic properties of fine particles in inhaled preparations (General Rule 0951), the FPF should not be less than 15% of the labeled dose.

[0175] Table 9. MMAD, GSD, and FPF values ​​output by the analysis software after importing the drug content detection values ​​of each component in the ACI experiment.

[0176]

[0177] Example 3: Compatibility study of riociguat active pharmaceutical ingredient with ethanol:

[0178] The table below shows the changes in impurity content when riociguat API and ethanol solvent are mixed at a mass ratio of 1:1 and stored at 25℃ / 60% RH and 40℃ / 75% RH. It can be seen that riociguat API and ethanol solvent are compatible and stable.

[0179] Table 10. Compatibility Study of Riociguat API with Ethanol

[0180]

[0181] Example 4: Stability study of Riociguat aerosol samples:

[0182] The table below shows the changes in impurity content of Riociguat aerosol samples (formulation numbers 1, 2, and 3) in Example 2 under storage conditions of 25°C / 60% RH and 40°C / 75% RH:

[0183] Table 11. Samples of the prescribed Riociguat aerosol.

[0184]

[0185] Example 5: Comparison of atomization morphology of Riociguat suspension aerosol

[0186] The spray pattern of inhaled aerosol products directly affects the distribution and deposition of drugs in the respiratory tract. Evaluating the spray pattern is crucial for assessing whether inhaled aerosol products effectively deliver drugs and achieve good therapeutic effects. Inhaled aerosol products are drug-device combinations; the component parameters of the driver assembly in the aerosol device—the nozzle diameter and nozzle length—directly influence the spray pattern. Optimizing these parameters improves the spray pattern, thereby enhancing drug delivery efficiency and product quality. In this embodiment, the formulation prepared in Example 2 is used as the research object, with different aerosol device driver parameter variables set. Specifically, in Example 2, formulations 1-3 use driver parameters of a nozzle diameter of 0.35 mm and a nozzle length of 0.7 mm; formulations 4-5 use driver parameters of a nozzle diameter of 0.30 mm and a nozzle length of 1.0 mm. After setting the trigger parameters, camera parameters, and laser parameters in the spray pattern analyzer (manufactured by Proveris, USA), the images acquired by the spray pattern analyzer are processed using Viora software, and parameters describing the spray pattern characteristics, such as spray velocity, spray angle, and plume duration, are analyzed and calculated. The specific spray patterns of prescriptions 1-5 in Example 2 collected in this implementation scheme are shown in the table below, providing an exemplary example. Figures 9-13 .

[0187] Table 12. Spray Formulations of Each Formula

[0188]

[0189] Note: In the table above, 30mm height indicates that the spray test is conducted at a height of 30mm from the detector, and the spray area is measured. 60mm height indicates that the spray test is conducted at a height of 60mm from the detector, and the spray area is measured. 60mm distance indicates that the spray test is conducted at a distance of 60mm from the detector, and the spray fan angle and atomization pattern are measured. Dmin represents the minimum diameter of the atomized area, Dmax represents the maximum diameter of the atomized area, Area represents the atomized area, Arm1 represents the separation angle on the atomized fan surface (the angle between the upper edge of the fan surface and the horizontal line in the middle of the fan surface), Arm2 represents the lower separation angle on the atomized fan surface (the angle between the lower edge of the fan surface and the horizontal line in the middle of the fan surface), angle represents the total angle of the atomized fan surface, and width represents the maximum vertical width of the atomized fan surface.

[0190] The above results, which show the detection of aerosol atomization morphology, are used to determine the influence of different formulations and equipment on changes in aerosol atomization morphology.

[0191] Example 6: Preparation of Riociguat suspension-type inhalation aerosol

[0192] Dissolve the prescribed amount of surfactant and suspending agent in the dispersant. After thorough stirring and dissolution, add the prescribed amount of riociguat drug granules (granules number 5 in Table 6 of Example 1). Control the stirring speed to 4000 rpm and the stirring time to 5 min. Dispense the thoroughly mixed dispersion into aluminum cans and fill them with the prescribed amount of propellant through the valve installed on the can. The propellant is selected from HFA-134a, HFO-1234ze and HFA-152a. One hundred bottles of riociguat suspension-type inhalation aerosol with theoretical drug doses of 100 μg / puff and 200 μg / puff were prepared (in actual preparation, 25% of the raw material needs to be overfilled to achieve the rated drug dose per puff). Table 13 below shows the formulation composition and nozzle diameter / length characteristic parameters of the inhalation device for 100 bottles of riociguat inhalation aerosol prepared according to the above method; Table 14 shows the MMAD, GSD, and FPF parameters of the corresponding formulation detected by the ACI equipment in the fine particle dose experiment.

[0193] Table 13. Formulation composition of Riociguat inhaler and characteristic parameters of nozzle diameter / length of inhalation device.

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] Table 14 and Table 13 show the corresponding MMAD, GSD, and FPF test values ​​for each prescription.

[0201]

[0202]

[0203]

[0204] Example 7: Stability study of Riociguat aerosol samples:

[0205] The table below lists the changes in impurity content and FPF (Fast Processing Factor) values ​​of the riociguat aerosol samples with 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, stored under conditions of 25°C / 60% RH and 40°C / 75% RH:

[0206] Table 15. Stability Study of Leocicgua Aerosol Samples

[0207]

[0208]

[0209]

[0210] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. An inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, characterized in that, Include: SGC receptor agonist or a pharmaceutically acceptable salt thereof; and at least one inhalation excipient that can be aerosolized.

2. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to claim 1, characterized in that, The dosage forms of the pharmaceutical composition include inhaled aerosols, inhaled powders, inhaled sprays, inhaled liquid formulations, inhaled soft fogs, or formulations that can be converted into vapors. Preferably, it is a suspension-type inhalation aerosol.

3. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to claim 1 or 2, characterized in that, In the pharmaceutical composition, the SGC receptor agonist or a pharmaceutically acceptable salt thereof is present in particulate or solution form; And / or, the inhaled pharmaceutical excipients include surfactants, propellants, dispersants and / or suspending agents.

4. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to claim 3, characterized in that, When the SGC receptor agonist or its pharmaceutically acceptable salt is present in particulate form, its particle size distribution D50 ranges from 0.1 to 10 μm. Preferably, its particle size distribution D50 ranges from 0.1 to 5 μm.

5. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to claim 4, characterized in that, 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 excipients include lecithin and / or distearate 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 containing a soluble guanylate cyclase receptor agonist according to any one of claims 3-5, characterized in that, 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 containing a soluble guanylate cyclase receptor agonist according to any one of claims 3-6, characterized in that, 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 containing a soluble guanylate cyclase receptor agonist according to any one of claims 3-7, characterized in that, The suspending agent is selected from polyvinylpyrrolidone; 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 0-5% wt.

9. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to any one of claims 3-8, characterized in that, The SGC receptor agonist or a pharmaceutically acceptable salt thereof includes, but is not limited to, at least one of riociguat, vericaccum, and palicaccum; Preferably, the SGC receptor agonist or a pharmaceutically acceptable salt thereof is riociguat.

10. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to any one of claims 3-9, characterized in that, In the pharmaceutical composition, the content of the SGC receptor agonist or its pharmaceutically acceptable salt ranges from 0.01% to 20% wt, the content of the surfactant is 0% to 5% wt, the content of the propellant is 50% to 99.9999% wt, the content of the dispersant is 0% to 30% wt, and the content of the suspending agent is 0% to 5% wt. Optionally, the SGC receptor agonist or a pharmaceutically acceptable salt thereof in the pharmaceutical composition ranges from 25 to 1000 μg / puff.

11. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to any one of claims 3-10, characterized in that, The inhalation device for the drug composition includes an inhalation device comprising a metering valve, an actuator, an adapter, a nozzle, a canister, a metering counter, and other necessary components.

12. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to claim 11, characterized in that, The nozzle diameter of the actuator ranges from 0.15 to 0.7 mm, and the nozzle length ranges from 0.3 to 2 mm. Preferably, the nozzle diameter of the actuator is in the range of 0.3-0.4 mm, and the nozzle length is in the range of 0.6-1.0 mm.

13. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to any one of claims 1-12, characterized in that, When the pharmaceutical composition is applied, its spray parameters 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 particle size of the aerosol particles ranges from 1 to 10 μm; preferably, it is 1 to 5 μm.

14. The inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to any one of claims 1-13, characterized in that, When the pharmaceutical composition is administered, T max The value is 5 min to 30 min; Preferably, it also includes a method for preparing the inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist, comprising: preparing a dosage form acceptable in the pharmaceutical field according to the formulation.

15. The use of the inhalable pharmaceutical composition containing a soluble guanylate cyclase receptor agonist according to any one of claims 1-14 in any of the following: Use in the preparation of medicaments for the prevention and treatment of Class I pulmonary hypertension; Class I pulmonary hypertension includes arterial pulmonary hypertension (PAH); Use in the preparation of medicaments for the prevention and treatment of Class IV pulmonary hypertension; said Class IV pulmonary hypertension includes chronic thromboembolic pulmonary hypertension (CTEPH); Use in the preparation of medicaments for the prevention and treatment of Class III pulmonary hypertension; said Class III pulmonary hypertension includes pulmonary hypertension caused by respiratory diseases; said pulmonary hypertension caused by respiratory diseases includes pulmonary hypertension PH-COPD caused by chronic obstructive pulmonary disease; or, pulmonary hypertension PH-ILD caused by idiopathic interstitial lung disease.

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