Inhalation soft mist formulations containing riociguat and methods of making and using the same

Abstract

The present application provides a dosing regimen for delivering riociguat by an inhalation soft mist device, aiming to provide an effective dose of riociguat on demand by a portable and easy-to-use inhalation soft mist device, so as to achieve a rapid onset of action after administration, and to enable pulmonary arterial hypertension patients to manage their condition more flexibly in daily life, improve exercise tolerance and overall health. The present application relates to a liquid, propellant-free riociguat pharmaceutical preparation, aiming to be administered by inhalation through a soft mist inhalation device. The pharmaceutical preparation comprises: (a) riociguat or a pharmaceutically acceptable salt thereof; (b) a solvent; (c) pharmaceutically acceptable adjuvants such as: solubilizers and preservatives; etc. The pharmaceutical preparation of the present application has a low inspiratory flow rate requirement, and the patient only needs to breathe naturally to achieve sufficient deposition of the drug in the lungs, thereby improving the bioavailability of the drug.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically to compositions containing riociguat and methods for their preparation. Background Technology

[0002] Pulmonary arterial hypertension (PAH) is a progressively severe disease characterized by pulmonary vascular remodeling and narrowing. This remodeling leads to elevated pulmonary artery pressure, affecting cardiac function and potentially causing heart failure. PAH has diverse causes, including idiopathic PAH, hereditary PAH, drug- or toxin-induced PAH, and PAH associated with connective tissue diseases, HIV infection, or congenital heart disease. Genetic factors, hypoxia, inflammation, and other pathological factors combine to damage pulmonary artery endothelial cells. These alterations in endothelial cell function subsequently affect smooth muscle cell behavior. During the progression of PAH, smooth muscle cells in the pulmonary artery tissue undergo a transformation from a contractile phenotype to a proliferative phenotype—a process known as vascular remodeling. Vascular remodeling leads to thickening of the arterial wall, resulting in vascular narrowing and increased blood flow resistance.

[0003] Symptoms of PAH typically include shortness of breath, fatigue, chest pain, and fainting, significantly reducing patients' quality of life. Due to high pressure in the pulmonary arteries, local blood flow is obstructed, leading to reduced oxygen exchange efficiency in the lungs. Patients experience shortness of breath during daily activities, especially exercise, because the body's increased oxygen demand cannot be met by the lungs' blood supply. This shortness of breath forces patients to exert more effort to obtain sufficient oxygen, resulting in increased physical exertion. Simultaneously, the heart works harder under high stress, potentially leading to heart failure and further exacerbating fatigue. According to the World Health Organization (WHO) functional classification, PAH patients are generally divided into categories II to IV. Category II patients experience mild discomfort during daily activities, while Category IV patients experience discomfort even at rest.

[0004] Currently, treatments for PAH primarily involve drugs targeting the endothelin, prostacyclin, or nitric oxide pathways. These drugs aim to reduce vasoconstriction or promote vasodilation. Common treatments include phosphodiesterase 5 (PDE5) inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase (sGC) stimulators. SGC receptor agonists are a class of drugs that specifically bind to and activate the oxidized, heme-free, soluble guanylate cyclase (sGC) form, thereby promoting the production of intracellular cyclic guanosine monophosphate (cGMP). This mechanism is crucial for regulating vasodilation and improving cardiac function, showing potential particularly in the treatment of diseases such as heart failure and pulmonary hypertension (PAH). Currently, Riociguat is the only approved SGC receptor agonist for the treatment of PAH, possessing a dual mechanism of action: it can directly stimulate sGC independently of nitric oxide (NO), and by stabilizing the binding of NO to sGC, it increases the sensitivity of sGC to endogenous NO, thereby increasing intracellular cGMP levels. Compared to PDE5 inhibitors, riociguat has shown superior efficacy in treating PAH, especially in patients who have developed resistance to PDE5 inhibitors or are insensitive to NO signaling. Clinical studies such as the RESPITE trial have demonstrated that switching from PDE5 inhibitors to riociguat resulted in significant improvements in indicators such as 6-minute walk distance, NT-proBNP levels, and WHO functional classification.

[0005] As mentioned above, the pathophysiological characteristics of PAH are mainly concentrated in the pulmonary vessels, classifying it as a localized lesion. However, its effects are indeed systemic, as it further impacts cardiac function and overall blood circulation. Based on the pathophysiological characteristics of PAH, inhaled topical administration can directly deliver the active ingredient to the lungs, increasing the drug concentration at the target site and thus improving therapeutic efficacy. Simultaneously, inhaled topical administration can significantly reduce the drug's distribution throughout the body, minimizing the occurrence of systemic side effects.

[0006] Inhaled drug delivery regimens for the treatment of PAH have gained considerable clinical evidence in terms of improving the pharmacological properties of drugs, enhancing drug targeting and selectivity, and improving patient compliance. For example, inhaled prostacyclin receptor-targeting drugs such as treprostene and iloprost have been approved for marketing due to their unique clinical advantages. In addition, inhaled formulations of soluble guanylate cyclase (SGC) receptor agonists also show promising clinical application prospects. For instance, MK-5475, a representative SGC receptor agonist, has been approved for clinical trials in the treatment of PAH. In preclinical and clinical studies (NCT04609943), MK-5475 showed good tolerability, especially with no significant effect on systemic blood pressure at high doses. The development of MK-5475 provides scientific evidence and clinical support for inhaled formulations of sGC receptor agonists, demonstrating good therapeutic potential, particularly in the treatment of PAH and related cardiopulmonary diseases.

[0007] Riociguat, currently the only approved SGC receptor agonist for the treatment of PAH (percutaneous pulmonary edema), is available in oral tablet form. As a soluble guanylate cyclase (sGC) activator, riociguat targets the nitric oxide signaling pathway in pulmonary vascular cells, achieving vasodilation. Vasodilation allows for adequate oxygen exchange in the lung tissue, alleviating common PAH symptoms such as dyspnea, fatigue, and syncope.

[0008] Inhaled aerosols, a method of drug delivery to the lungs in aerosol form, has emerged in the last 20 years and is particularly suitable for treating respiratory diseases. Compared to traditional inhalation methods, the use of inhaled aerosols primarily aims to improve drug bioavailability and patient compliance. Compared to traditional inhalers (such as compressed aerosols) and dry powder inhalers, aerosols have a lower jet velocity and a longer spray duration, allowing for more effective delivery of drug particles to the lungs and reducing irritation to the throat and upper respiratory tract. Their working principle relies on liquid being pressurized by a pump, flowing into the nebulizer body, and forming a fine spray through multiple atomization orifices. The aerosol pushes the liquid drug at high pressure to the nozzle via a pump unit. The nozzle is typically designed as an impactor, generating fine aerosol droplets through the collision of at least two liquid jets. These droplets are typically in the range of a few micrometers in diameter, making them easy to inhale into the lungs. Aerosols are handheld devices designed for easy patient use and generally do not use chemical propellants, relying instead on mechanical pumping to generate pressure, thus reducing environmental impact. By optimizing nozzle design and drug formulation, soft aerosols can deliver drugs efficiently, ensuring an effective drug concentration in the lungs. Summary of the Invention

[0009] In light of the prior art described in the background information, there are some unmet clinical needs in the treatment of PAH disease, particularly with guanylate cyclase receptor (SGC) agonists such as oral riociguat. This invention selects a soft mist inhaler as the drug delivery device for inhaled administration of riociguat. Compared to traditional oral riociguat treatment for PAH, the inhaled soft mist administration regimen containing riociguat provided by this invention has the following characteristics and advantages:

[0010] 1. Convenience: Soft fogging devices are typically designed to be handheld and pocket-sized, making them convenient for patients to use anytime, anywhere;

[0011] 2. On-demand medication: Soft inhalers allow patients to inhale an effective dose of medication as needed, providing flexible treatment options, especially when experiencing symptoms of PAH disease;

[0012] 3. Rapid onset of action: Inhaled riociguat has good lung selectivity, which reduces the risk of systemic side effects and allows for a more rapid onset of action after administration;

[0013] 4. Superior user experience: Soft sprays are designed to simplify the administration process and reduce the complicated steps required for patients to use traditional nebulizers.

[0014] In summary, soft inhalers, as an innovative drug delivery device, offer a portable, rapid, and flexible method of drug delivery, making them particularly suitable for patients with pulmonary hypertension requiring on-demand treatment. By using soft inhalers to deliver riociguat, patients can manage their symptoms more effectively and improve their quality of life. Attached Figure Description

[0015] Figure 1 This is a distribution diagram of drug content in each fraction of the NGI test for the liociguat soft spray sample. Detailed Implementation

[0016] The present invention relates to an inhaled soft fogging agent containing riociguat and a method for preparing the same, with the aim of using a convenient soft fogging inhaler device to deliver riociguat to improve the quality of life of patients with pulmonary hypertension.

[0017] One aspect of the present invention is to provide an inhaled soft fogging agent containing riociguat. This inhaled soft fogging agent exhibits good drug stability and suitable inhalation characteristics, and can be conveniently used by patients via aerosolization using a soft fogging inhaler device.

[0018] Specifically, by mass percentage, the Riocigua soft mist agent comprises the following components: 0.004‰ to 3% Riocigua, 0.01% to 10% pH adjuster, and the balance of solvent;

[0019] Preferably, the riociguat soft mist agent comprises the following components: 0.004‰ to 3% riociguat, 0.05% to 5% pH adjuster, and the balance solvent;

[0020] Furthermore, the solvent may be ethanol, purified water, or a mixture of ethanol and purified water;

[0021] Furthermore, the riociguat drug component can be in the form of a pharmaceutically acceptable salt;

[0022] Furthermore, the riociguat soft mist formulation comprises the following components: 0.004‰ to 3% riociguat, 0.01% to 10% pH adjuster and the balance solvent; and at least one of other pharmaceutically acceptable excipients such as: solubilizers, surfactants, preservatives, antibacterial agents and osmotic pressure regulators;

[0023] Furthermore, the solubilizer may be selected from hydrophilic solvents, such as propylene glycol and other polyol solvents;

[0024] Furthermore, the antibacterial agent and preservative may be selected from at least one of the following: m-cresol, sodium benzoate, chlorhexidine, chlorhexidine gluconate, and benzalkonium chloride;

[0025] Furthermore, the osmotic pressure regulator may be selected from at least one of sodium chloride, magnesium chloride, glucose, phosphate, and citrate;

[0026] Furthermore, the surfactant can be selected from nonionic surfactants, such as polysorbates, polyvinyl alcohol (PVA), polyvinyl alcohol and polyvinylpyrrolidone (PVP); amphoteric surfactants such as phospholipids: dilauroyl phosphatidylcholine (DLPC), dipalmitoyl phosphatidylcholine (DPPC), distearate phosphatidylglycerol (DTPA), hydrogenated soybean phosphatidylcholine (HSPC) and soybean phosphatidylcholine (SPC);

[0027] Furthermore, the pharmaceutically acceptable pharmaceutical excipient may be selected from cyclodextrin components, which form inclusion complexes or complexes with poorly soluble drug molecules to improve drug solubility;

[0028] Furthermore, the pH adjuster may be selected from: hydrochloric acid, acetic acid, citric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, phosphate buffer, acetate-sodium acetate buffer, and ammonia-amino acid buffer;

[0029] Furthermore, the pharmaceutical preparation containing the riociguat drug composition is a true solution;

[0030] Furthermore, the pharmaceutical formulation of the riociguat-containing drug composition is prepared as a nano-suspension;

[0031] One aspect of the present invention is to provide an inhaled soft aerosol containing riociguat. In a specific administration embodiment, the liquid containing the drug to be atomized and delivered in the inhaled aerosol contains 5 μg to 500 μg of riociguat per spray.

[0032] Furthermore, the preferred range of riociguat drug content per spray is 50 μg to 400 μg;

[0033] Furthermore, the volume of the riociguat-containing liquid delivered per spray is at least about 1 μL, 2 μL, 5 μL, 10 μL, 15 μL, 20 μL, 25 μL, 30 μL, 50 μL, 100 μL, 500 μL, or 1000 μL.

[0034] Furthermore, the volume of the riociguat-containing liquid delivered per spray is in the range of about 1 μL to about 1000 μL, about 2 μL to about 30 μL, about 5 μL to about 25 μL, and about 10 μL to about 20 μL.

[0035] Furthermore, the concentration of the riociguat-containing drug delivered per spray can be selected from about 5 μg / μL to about 100 μg / μL, specifically from about 7.5 μg / μL to about 90 μg / μL, or from about 10 μg / μL to about 85 μg / μL;

[0036] One aspect of the present invention is to provide an inhalation soft fog formulation containing riociguat. The drug is administered by nebulization inhalation by loading the riociguat-containing drug formulation into a soft fog inhaler device.

[0037] Furthermore, the soft atomizing device uses mechanical force to force the unpressurized drug formulation through a dual-channel nozzle, forming two converging jets. These jets meet at a specific angle, breaking the drug solution into inhalable droplets. The mechanical energy required for atomization is generated by rotating the bottom of the device 180° to establish spring tension. When the patient activates the device, the energy released by the spring applies pressure to the flexible drug container, forcing a certain dose of liquid through the nozzle to form aerosol particles.

[0038] Furthermore, through the micro-engineered nozzle design of the soft atomizing device, the drug solution is dispersed into inhalable droplets using the Rayleigh splitting principle. The device mechanically forces the drug solution into the nozzle, with the mechanical energy for atomization provided by a spring that loads and releases the patient. The drug solution can be stored in a container with a mechanical pump system or pre-filled in a glass syringe.

[0039] Furthermore, the basic structural components of a soft mist device include: an atomizer body, a valve device, a liquid passage, and a working cross-section;

[0040] Furthermore, the basic structural components of the soft mist device include: a sprayer, a liquid container, a liquid compartment, a pressure generator, a support and drive spring, a delivery pipe, a positive valve, and a nozzle.

[0041] Furthermore, the liquid containing riociguat is pressurized and delivered to the nebulizer body via a pump. The valve opens when the applied liquid pressure reaches a predetermined threshold, and the valve body moves within the valve chamber to control the liquid passage between the valve and the nebulizer body. The valve body is held closed by the counter-pressure of a spring mechanism; only after reaching a certain liquid pressure can the valve body overcome the spring's counter-pressure and open, allowing liquid flow. When the valve body opens, the liquid is ejected as fine droplets through the atomization opening of the nebulizer body, forming an atomized spray.

[0042] One aspect of the present invention is to provide an inhaled soft fog formulation containing riociguat. Using a portable soft fog inhaler, patients can conveniently self-administer the medication, meeting their daily needs and improving their quality of life.

[0043] Furthermore, the inhaled soft fog containing riociguat can be used in the preparation of medicines for the prevention and treatment of pulmonary arterial hypertension (WHO Group 1); pulmonary arterial hypertension (WHO Group 1) includes arterial pulmonary hypertension (PAH).

[0044] Furthermore, the inhaled soft fog containing riociguat can be used 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).

[0045] Furthermore, the inhaled soft fogging formulation containing riociguat can be used in the preparation of medicines for the prevention and treatment of pulmonary hypertension of Group 3 (WHO Group 3); said Group 3 pulmonary hypertension includes pulmonary hypertension caused by respiratory diseases; said 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).

[0046] Experiment Example 1: Prescription Screening

[0047] 1. Preparation steps of soft fog formulation:

[0048] a. Dissolve the pharmaceutical excipients in purified water to obtain solution 1;

[0049] b. Add riociguat to solution 1 and stir well to obtain solution 2;

[0050] c. Add an appropriate amount of at least one of the following: surfactant, antibacterial agent, preservative or osmotic pressure regulator to solution 2, and stir thoroughly to obtain solution 3;

[0051] d. Add pH adjuster to solution 3 to adjust the pH to 4.0;

[0052] e. Add the remaining purified water, filter, sterilize, and seal.

[0053] Table 1

[0054]

[0055]

[0056] 2. Preparation steps of soft fog formulation:

[0057] a. Dissolve the pharmaceutical excipients in a mixed solvent of ethanol and water to obtain solution 1;

[0058] b. Add riociguat to solution 1 and stir well to obtain solution 2;

[0059] c. Add an appropriate amount of at least one of the following: surfactant, antibacterial agent, preservative or osmotic pressure regulator to solution 2, and stir thoroughly to obtain solution 3;

[0060] d. Add pH adjuster to solution 3 to adjust the pH to 4.0;

[0061] e. Add the remaining ethanol and water mixture, filter, sterilize, and seal.

[0062] Table 2

[0063]

[0064]

[0065] Example 2: Stability

[0066] The stability of the samples in the examples was tested. These samples were stored at 15°C–25°C for 6 months, 12 months, and 24 months, and their content was determined. The results showed that the changes in the sample content at different time points indicated their chemical stability.

[0067] Table 3 Results of stability study of samples 1-41

[0068]

[0069]

[0070]

[0071] Example 3: Atomization Index Detection

[0072] The liociguat soft aerosol samples from Examples 38, 39, 40, and 41 were selected. Detection equipment: A new generation cascade impactor (NGI) was used to simulate the structure of the human respiratory tract for fine particle aerodynamic characterization. Detection procedure: Each sample was loaded into a soft aerosol device and nebulized according to standard operating procedures. The aerosol was collected and fractionated using an NGI instrument. The drug content of each fraction was determined to calculate the fine particle fraction (FPF) and delivery efficiency. The drug content data for each fraction were recorded and analyzed as follows. Figure 1 As shown.

Claims

1. An inhaled soft fogging agent containing riociguat, characterized in that, Contains: riocigua or its pharmaceutically acceptable salts, solvents, and aerosolizable inhalation excipients.

2. The inhaled soft fogging agent containing riociguat according to claim 1, characterized in that, The solvent is selected from purified water, ethanol, and mixtures thereof.

3. The inhaled soft fogging agent containing riociguat according to claim 1, characterized in that, The excipients for the inhaled medication are characterized by being selected from solubilizers, surfactants, preservatives, pH adjusters, antibacterial agents, and osmotic pressure regulators.

4. The inhaled soft fogging agent containing riociguat according to claim 3, characterized in that, The pH adjuster is selected from hydrochloric acid, citric acid, benzoic acid, acetic acid, sodium dihydrogen phosphate, sodium citrate, sodium acetate, and sodium hydroxide.

5. The inhaled soft fogging agent containing riociguat according to claim 3, characterized in that, The surfactant is selected from Tween 80, Tween 20, Span 20, glycerol, poloxamer, phospholipids and oleic acid.

6. The inhaled soft fogging agent containing riociguat according to claim 3, characterized in that, The osmotic pressure regulator is selected from one or more of sodium chloride, magnesium chloride, glucose, phosphate, or citrate.

7. The inhaled soft fogging agent containing riociguat according to claim 3, characterized in that, The solubilizer is selected from hydrophilic solvents, such as propylene glycol and other polyol solvents; the preservative is selected from at least one of m-cresol, sodium benzoate, chlorhexidine, chlorhexidine gluconate and benzalkonium chloride; the antibacterial agent is selected from at least one of m-cresol, sodium benzoate, chlorhexidine, chlorhexidine gluconate and benzalkonium chloride.

8. The inhaled soft fogging agent containing riociguat according to any one of claims 1-7, characterized in that: By weight percentage, it comprises the following components: riociguat (0.004‰–3%), pH adjuster (0.05%–5%), surfactant (0%–5%), antibacterial agent (0%–1%), preservative (0%–1%), and osmotic pressure regulator (0%–5%), and solvent to make up the balance to 100%.

9. The inhaled soft fogging agent containing riociguat according to any one of claims 1-7, characterized in that: The particle size D50 ranges from 1 to 5 μm, and the D90 ranges from 1 to 10 μm.

10. The riociguat-containing drug inhalation soft fogging agent according to claims 1-7, characterized in that: The spray volume per application is 1–100 μL, and the dosage per application is 10–1000 μg.

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