Pulmonary arterial hypertension treatment method

Abstract

In accordance with embodiments of the invention, a method of treating pulmonary arterial hypertension comprises administering to a subject in need thereof a therapeutically effective amount of vardenafil or a pharmaceutically acceptable salt or hydrate thereof. According to the method, a portable inhaler is used for on-demand inhalation administration, and the vasodilator needs to be applied 2-30 minutes before physical activity.

Description

Cross Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 470,091, filed May 31, 2023, entitled “Pulmonary Hypertension Treatment Method,” which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] The present invention relates to methods and compositions for pulmonary hypertension subjects, and devices related to these methods and compositions. BACKGROUND

[0003] Pulmonary hypertension (PH) is a rare disease characterized by abnormally elevated pulmonary arterial pressure and pulmonary vascular resistance (PVR). Pulmonary arterial hypertension (PAH), the first class of pulmonary hypertension, is a progressive disease of unknown etiology. It is characterized by a mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg, a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg, a pulmonary vascular resistance (PVR) ≥ 3 Wood units, and a physiological change in the pulmonary artery. As the disease progresses, patients’ exercise capacity gradually decreases, and daily activities become increasingly difficult.

[0004] There is currently no cure for pulmonary hypertension. Existing treatment options include approved endothelin receptor antagonists, phosphodiesterase type 5 inhibitors (PDE5i), and prostacyclin analogs, which can alleviate symptoms and slow disease progression.

[0005] For patients with pulmonary hypertension, it is always a serious challenge to control acute symptoms triggered by daily activities, as none of the approved therapies can be used for acute symptom relief. The current standard treatment for pulmonary hypertension is long-term therapy that requires multiple doses, aiming to alleviate symptoms and slow disease progression. Despite these improvements, patients’ cardiopulmonary fitness and exercise capacity still decrease significantly. These treatments are also associated with adverse reactions that reduce patients’ quality of life, including nausea, headache, flushing, and injection site pain and infection caused by infusion of the drug. These adverse reactions are partly due to the high dose required to achieve an effective local drug concentration in the pulmonary artery.

[0006] Therefore, there is an urgent clinical need for a pulmonary hypertension treatment method that can be used on an as-needed (PRN) basis to relieve acute symptoms and help patients with daily activities and exercise. SUMMARY

[0007] According to embodiments of the present invention, a method of treating pulmonary hypertension includes administering to a subject in need thereof a therapeutically effective amount of vardenafil or a pharmaceutically acceptable salt or hydrate thereof. The method is administered by a portable inhaler on an as-needed basis, and the vasodilator is administered 2-30 minutes before physical activity.

[0008] In particular embodiments, the administration of vardenafil includes targeted delivery to the small airways of the lung of the subject. In further embodiments, the nominal dose of vardenafil delivered to the subject upon inhalation is about 0.5 mg to about 1 mg. In one embodiment of the application, the nominal dose of vardenafil delivered to the subject upon inhalation is about 0.5 mg. Alternatively, in another embodiment of the application, the nominal dose of vardenafil delivered to the subject upon inhalation is about 1.0 mg. DETAILED DESCRIPTION

[0009] The present application relates to methods and compositions useful for patients with pulmonary arterial hypertension, as well as devices associated with these methods and compositions. The methods include on-demand administration of a phosphodiesterase type 5 inhibitor (PDE5i) by inhalation. In some embodiments, the phosphodiesterase type 5 inhibitor is vardenafil.

[0010] The methods disclosed herein provide pulmonary targeted therapy for patients with pulmonary arterial hypertension and other forms of pulmonary arterial hypertension or other pulmonary diseases, delivering the drug to the pulmonary vascular bed by dry powder inhaler with minimal systemic exposure. Such an inhaled drug should have good pulmonary tolerability and minimal or no systemic exposure, suitable for both daily 1, 2, 3 or more times of targeted long-term maintenance therapy, and the potential for on-demand use.

[0011] A pulmonary arterial hypertension on-demand drug that is easy to use and portable, allowing patients to easily improve short-term function and exercise tolerance to perform activities of daily living (ADL) or other more strenuous activities. By avoiding the risk of ventilation / perfusion mismatching associated with systemic (enteral or parenteral) administration of pulmonary vasodilators and dose-limiting systemic side effects, the portable inhaler drug delivery method of the present application with inhaled pulmonary vasodilators significantly improves the functional status and quality of life of patients with limited activity due to pulmonary arterial hypertension and / or interstitial lung disease (ILD).

[0012] In some embodiments, patients self-administer a lower dose of a drug (e.g., inhaled vardenafil, a phosphodiesterase type 5 inhibitor) via the inhaled route as on-demand therapy on top of long-term therapy, allowing for improved exercise tolerance throughout the day while minimizing the risk of systemic side effects. On-demand drug delivery requires that the drug product be highly targeted to the lung and pulmonary vasculature while minimizing drug concentrations in the systemic circulation to avoid causing systemic hypotension. Inhaled aerosol delivery also has the advantage of rapid onset of action (comparable to injection) compared to oral administration.

[0013] By administering inhaled vasodilators on demand, patients with pulmonary hypertension can self-administer lower nominal doses of the medication before increasing their activity levels. This allows for the safe and effective improvement of quality of life and daily functional indicators, while optimizing the efficacy of basic treatments and enhancing daily living abilities.

[0014] Methods and compositions for treating pulmonary hypertension and other lung diseases (including methods and compositions involving type 5 phosphodiesterase inhibitors such as vardenafil) are disclosed in U.S. Patent No. 10,912,778 (titled “Treatment for Pulmonary Hypertension”), the entire contents of which are incorporated herein by reference. Type 5 phosphodiesterase inhibitors

[0015] Phosphodiesterase type 5 (PDE5) inhibitors block the degradation of cyclic guanosine monophosphate (cGMP) by inhibiting the activity of PDE5. The pathological mechanism of pulmonary hypertension is closely related to the decreased cGMP concentration in pulmonary vascular smooth muscle due to impaired endothelial nitric oxide (NO) release. PDE5 is the most prevalent phosphodiesterase subtype in the pulmonary vascular system. PDE5 inhibitors increase cGMP concentration by inhibiting PDE5, thereby causing relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed. PDE5 inhibitors suitable for embodiments of this invention include: sildenafil, tadalafil, vardenafil, avanafil, benzamide nafil, lodenafil, milodenafil, udenafil, and zaplastase.

[0016] In one embodiment of the invention, the type 5 phosphodiesterase drug is vardenafil (i.e., 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethylpiperazine, or a pharmaceutically acceptable salt thereof such as monohydrochloride). Vardenafil and other 2-phenyl-substituted imidazotriazinone compounds are described, for example, in U.S. Patents 6,890,922, 7,122,540, 7,314,871, 7,704,999, and 7,696,206, the entire contents of which are incorporated herein by reference. Clinical studies have demonstrated the safety and efficacy of vardenafil when administered orally twice daily at 5 mg per dose in patients with pulmonary hypertension. Compared to sildenafil and tadalafil, vardenafil exhibits superior inhalation delivery characteristics and has been successfully formulated into a dry powder preparation for administration via a dry powder inhaler (for details of the technical solution, please refer to International PCT Application WO / 2015 / 089105 and US Patent Application 2016 / 0317542, the full text of which is incorporated herein by reference). Vardenafil has a high affinity inhibitory effect on phosphodiesterase type 5 (IC50, 50% inhibitory concentration [IC50]). 50[0.091±0.031]. Instructions for use of type 5 phosphodiesterase inhibitors

[0017] The vasodilators disclosed in this article primarily act on smooth muscle cells within the pulmonary artery and arterioles. A key objective of on-demand drug therapy is to maximize drug delivery to the pulmonary artery while minimizing off-target delivery (avoiding swallowing) in the mouth and throat, thereby reducing safety and tolerability risks. For inhaled therapy, improving pulmonary targeting can be achieved not only by optimizing pulmonary drug delivery efficiency but also through the rational design and / or screening of drugs to be delivered.

[0018] On-demand lung-targeted therapies may have fundamentally different design goals than oral therapies. Oral therapies aim to maximize and maintain drug concentrations in the systemic circulation. This is achieved by increasing oral bioavailability while maintaining systemic concentrations of the "free" drug by reducing protein binding and systemic clearance. In contrast, on-demand lung therapies aim to prolong lung retention time by extending drug-receptor binding time, slowing the rate of drug dissolution in alveolar epithelial lining fluid, or developing controlled-release formulations (such as liposomes). Once absorbed into the systemic circulation, the systemic effects should be minimized through rapid clearance and / or plasma protein binding. Furthermore, reducing oral bioavailability is also crucial for reducing systemic drug concentrations caused by inhaled drugs deposited in the upper respiratory tract. Vardenafil, with its slow dissociation rate and rapid clearance, is ideal for on-demand administration. Inhalation device for type 5 phosphodiesterase inhibitor powder

[0019] Lung delivery enables non-invasive, targeted delivery of vasodilators, directly delivering the drug to the lung site of action, thereby enhancing lung selectivity and reducing off-target delivery-related adverse events. Portable aerosol delivery systems are particularly suitable for on-demand administration of vasodilators. In this specification, a "portable" inhaler refers to an inhalation device that can be easily placed in a pocket or handbag. Portable inhalers with short dosing times can be used discreetly in public places. The methods and compositions according to embodiments of the present invention can employ portable, simple, and easy-to-use drug delivery devices (e.g., no power supply required, no active agent reconstitution step required, and no cleaning required), thereby enabling short-duration dosing and reducing the burden of daily treatment.

[0020] The compositions disclosed herein can be administered via various portable inhalers, including dry powder inhalers, pressurized metered-dose inhalers, and smart nebulizers.

[0021] In some embodiments, a high-efficiency dry powder inhaler (DPI) can be used to deliver vasodilators to a patient. In some embodiments, the inhaler is described in U.S. Patent Nos. 8,651,104; 8,561,609; U.S. Patent Application Nos. 2013 / 0213397, 2015 / 0246189, 2013 / 0340747; and 2015 / 0314086, each of which is incorporated herein by reference in its entirety for all purposes. Such inhalers can enhance the delivery of various dry powder drug compositions and, in some cases, deliver purely micronized drugs, such as the phosphodiesterase type 5 inhibitor vardenafil or vardenafil hydrochloride powder.

[0022] In some aspects, a method for nebulizing a dry powder composition is provided. The first step involves providing a carrier-type powdered drug composition comprising a vasodilator (e.g., a phosphodiesterase type 5 inhibitor or a pharmaceutically acceptable salt, hydrate, or ester thereof). The second step involves providing an inhaler comprising a dispersion chamber having an inlet and an outlet, and a actuator reciprocating within the dispersion chamber along its longitudinal axis. The first and second steps can be performed in any order or simultaneously. The third step involves inducing an airflow through the outlet channel, allowing air and the powdered drug composition to enter the dispersion chamber from the inlet, and driving the actuator to oscillate within the dispersion chamber to promote dispersion of the powdered drug composition from the outlet, thereby delivering the drug to a subject through the outlet. In some embodiments, the powdered drug may be stored in a storage chamber (of the inhaler), from which the powdered drug composition is transferred via the inlet to the dispersion chamber. In certain cases, the inlet may be in fluid communication with an initial chamber, into which the powdered drug composition enters the initial chamber before entering the dispersion chamber via the inlet.

[0023] In practice, patients can activate the nebulizer by puncturing the container holding the formulation (such as a capsule or blister pack) or by transferring the medication from the powder reservoir to the inhalation section of the device. During inhalation, the powder is drawn into the inhaler, fluidized through powder entrainment, and powder agglomerates are depolymerized into inhalable particles. This method is effective for dispersing binary and ternary carrier-based compositions, as well as formulations containing engineered particles.

[0024] Exemplary devices for administering dry powder compositions include dry powder inhalers and metered-dose inhalers, such as, but not limited to, those for administering dry powder compositions. (Merck) (GlaxoSmithKline) (Boehringer Ingelheim) (AstraZeneca) (AstraZeneca) (Novartis) (Novartis) (Eurogalon) (Meda Pharmaceuticals) (GlaxoSmithKline, etc.) As those skilled in the art will know, different devices have different performance characteristics due to factors such as device resistance, depolymerization mechanism, drug adhesion in the internal flow channel, and patient coordination of inhalation.

[0025] In some embodiments, the dry powder composition can be administered via a dry powder inhaler that includes a dry powder deagglomerator (also known as a powder dispersion mechanism). Exemplary powder dispersion mechanisms are detailed in U.S. Patent Publications 2013 / 0340754 and 2013 / 0340747, the entire contents of which are incorporated herein by reference. In some embodiments, such a powder dispersion mechanism may include beads disposed within a chamber designed to induce sudden, rapid, or abrupt expansion upon airflow. Typically, the chamber can be connected to any form of dose-acceptance system or to provide a source of the powdered active agent.

[0026] In some embodiments, the powder dispersion mechanism may be connected to a commercially available dry powder inhaler. The dispersion mechanism (dispersion chamber) may be configured to receive atomized powdered active agent from an inlet channel, such as the embodiment described in U.S. Patent Publication No. 2013 / 0340754 (the entire contents of which are incorporated herein by reference). The powder dispersion mechanism (dry powder deagglomerator) may be configured to receive at least partially atomized powdered active agent from a first chamber of the inhaler. The powder dispersion mechanism may include a dispersion chamber in which an actuator is disposed, movable along a longitudinal axis within the dispersion chamber. The dry powder inhaler may have an outlet channel for exhausting air and the powdered active agent and delivering it to the subject. The geometry of the inhaler may create a specific flow profile within the dispersion chamber, causing the actuator to oscillate along the longitudinal axis, thereby effectively dispersing the powdered drug within the dispersion chamber by the oscillating actuator and delivering it to the patient through the outlet channel.

[0027] In some embodiments, a dry powder inhaler system may be used to nebulize and administer a dry powder composition. The dry powder inhaler system may include a container holding a metered dose of a powdered active agent. The dry powder inhaler system may include an inlet channel adapted to receive air and powdered active agent from the container. The dry powder inhaler system may include a first chamber adapted to receive air and powdered active agent from the inlet channel. The volume of the first chamber may be larger than the volume of the inlet channel. The dry powder inhaler system may include a dispersion chamber adapted to receive air and powdered drug from the first chamber. The dispersion chamber may house a actuator movable within it along a longitudinal axis. The dry powder inhaler system may include an outlet channel through which air and powdered active agent exit the dispersion chamber and are delivered to the patient. The geometry of the system allows for a specific flow profile within the system, causing the actuator to oscillate along the longitudinal axis, thereby effectively dispersing the powdered drug within the dispersion chamber by the oscillating actuator and delivering it to the patient through the outlet channel. Administration and Dosage

[0028] The compositions and methods according to various embodiments of the present invention can provide dosage dosing regimens that do not require strict treatment protocols. Furthermore, medications designed for "on-demand" use can provide significant improvements for patients with poor adherence to long-term medication regimens or those experiencing decreased exercise tolerance at different times of the day due to their treatment regimen (even if they are fully following their doctor's orders). In this regard, on-demand medications can alleviate or improve symptoms in patients who miss doses, while allowing them to maintain their established treatment regimen. Using on-demand medications simplifies medication instructions regarding missed doses—for example, if a dose is missed, patients can be instructed to administer one dose of on-demand medication and then continue with their regular medication regimen for chronic conditions.

[0029] According to the embodiments of the present invention, after administration of the on-demand dosage form, patients can quickly experience symptom relief, and in some cases, near-immediate relief can be achieved. The on-demand dosage form involved in the embodiments of the present invention has the characteristic of rapid onset of action, for example, it can reach peak blood drug concentration in less than 15 minutes (e.g., less than 10 minutes or 5 minutes); and pharmacodynamic effects (such as improvement in hemodynamics, gas exchange and symptoms) can appear within 30 minutes after administration, with some measurable indicators showing improvement within 15 minutes or 10 minutes.

[0030] As described in this article, vasodilators administered via inhalation can achieve rapid onset of action, and their t max The value is much lower than 1 hour. For example, the t after inhalation of vardenafil via the lungs... max No more than 2 minutes. In contrast, the time to treatment with commonly used oral vasodilators is shorter. max Values ​​typically last 2-8 hours. Although intravenous injections allow drugs to enter the circulatory system immediately, their suitability as on-demand treatment is limited because: the administration method is highly invasive, it can lead to excessively high systemic drug concentrations causing significant adverse events, and patients cannot easily administer the medication on demand without using a complex pump system.

[0031] It is worth noting that the on-demand therapeutic drugs involved in the embodiments of the present invention can provide symptom relief and improved exercise tolerance for a duration sufficient to complete the target activity. Generally, the duration of this effect is at least 1 hour, and can be extended to more than 2 hours, more than 3 hours, or longer.

[0032] The on-demand therapeutic agents described in this invention maximize the amount of drug delivered to the pulmonary artery while minimizing off-target delivery (such as gastrointestinal and systemic delivery), thereby reducing safety and tolerability issues. Maximized lung-targeted delivery is achieved through oral inhalation of an aerosol. Given that this drug is administered in addition to basic treatment, the superior adverse event profile is a particularly important advantage of on-demand therapeutic agents. Injectable formulations can lead to excessively high systemic drug concentrations and significant adverse events, making them less suitable for on-demand dosing.

[0033] According to the method of the present invention, when a patient anticipates engaging in physical activity (such as exercise, walking, shopping trips, or other activities), the subject may administer an on-demand formulation containing a vasodilator (such as a phosphodiesterase type 5 drug) via inhalation. This formulation may be used alone or in combination with a second drug (co-formulation or individual packaging). Typically, the patient may administer the formulation 2–30 minutes before starting such activity. These doses may be added to the patient's existing chronic treatment regimen. The dosage of the aforementioned vasodilator or its combination may be sufficiently low to avoid significant additive side effects on the patient's baseline medication regimen, while simultaneously providing temporary pulmonary vasodilation for at least 30 minutes to 6 hours, thereby improving the patient's exercise tolerance and enabling them to perform their desired daily living activities.

[0034] In some embodiments, the on-demand therapeutic agent comprises one or more active agents in a nominal dose of 0.1-5.0 mg (e.g., 0.15-0.5 mg). In some embodiments, the on-demand therapeutic agent comprises one or more active agents in a nominal dose of 0.02-1.0 mg (e.g., 0.04-0.1 mg). As a non-limiting example, in an inhaled on-demand therapeutic agent formulated as a carrier and administered via a capsule-type dry powder inhaler, the nominal dose of vardenafil (base form) is typically about 0.1 mg to 2.0 mg (e.g., 0.15-0.50 mg).

[0035] This invention covers formulations of varying dosages, including formulations of type 5 phosphodiesterase inhibitor active agents delivered to the lungs at inhalation doses ranging from 0.01 mg to 5 mg.

[0036] For example, the inhaled doses of phosphodiesterase type 5 inhibitors can be 0.01-0.5 mg, 0.01-1 mg, 0.01-2 mg, 0.025-0.5 mg, 0.025-1 mg, 0.025-2 mg, 0.05-0.5 mg, 0.05-1 mg, 0.05-2 mg, 0.075-0.5 mg, 0.075-1 mg, 0.075-2 mg, 0.1-0.25 mg, 0.1-0.5 mg, 0.1-1 mg, 0.1-2 mg, 0.1-3 mg, 0.1-4 mg, 0.25-0.5 mg, 0.25-0.75 mg, 0.25-1 mg, 0.25- Doses of 1.5 mg, 0.25-2 mg, 0.25-3 mg, 0.25-4 mg, 0.5-0.75 mg, 0.5-1 mg, 0.5-2 mg, 0.5-1 mg, 0.5-2 mg, 0.5-3 mg, 0.5-4 mg, 0.75-1 mg, 0.75-2 mg, 0.75-1 mg, 0.75-2 mg, 0.75-3 mg, 0.75-4 mg, 1-1.5 mg, 1-2 mg, 1-2.5 mg, 1-3.5 mg, 1-4 mg, 2-3 mg, 2-4 mg, 0.5-4.5 mg, 2-5 mg, and doses within ±25% of these dosage ranges. In some such embodiments, the phosphodiesterase type 5 inhibitor is vardenafil.

[0037] In some embodiments, the inhaled dose of the type 5 phosphodiesterase inhibitor composition may be 0.01 mg, 0.25 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.225 mg, 0.25 mg, 0.275 mg, 0.3 mg, 0.325 mg, 0.35 mg, 0.375 mg, 0.4 mg, 0.425 mg, 0.45 mg, 0.5 mg, 0.525 mg, 0.55 mg, 0.575 mg, 0.6 mg, 0.625 mg, etc. mg, 0.65mg, 0.675mg, 0.7mg, 0.725mg, 0.75mg, 0.775mg, 0.8mg, 0.825mg, 0.85mg, 0.875mg, 0.9mg, 0.925mg, 0.95mg, 0.975m g, 1.0mg, 1.1mg, 1.15mg, 1.2mg, 1.25mg, 1.3mg, 1.35mg, 1.4mg, 1.45mg, 1.5mg, 1.55mg, 1.6mg, 1.65mg, 1.7mg, 1.75mg, 1.8m g, 1.85mg, 1.9mg, 1.95mg, 2.0mg, 2.1mg, 2.15mg, 2.2mg, 2.25mg, 2.3mg, 2.35mg, 2.4mg, 2.45mg, 2.5mg, 2.55mg, 2.6mg, 2.65 mg, 2.7mg, 2.75mg, 2.8mg, 2.85mg, 2.9mg, 2.95mg, 3.0mg, 3.1mg, 3.15mg, 3.2mg, 3.25mg, 3.3mg, 3.35mg, 3.4mg, 3.45mg, 3.5 The dosages are 3.55 mg, 3.6 mg, 3.65 mg, 3.7 mg, 3.75 mg, 3.8 mg, 3.85 mg, 3.9 mg, 3.95 mg, 4.0 mg, 4.1 mg, 4.15 mg, 4.2 mg, 4.25 mg, 4.3 mg, 4.35 mg, 4.4 mg, 4.45 mg, 4.5 mg, 4.55 mg, 4.6 mg, 4.65 mg, 4.7 mg, 4.75 mg, 4.8 mg, 4.85 mg, 4.9 mg, 4.95 mg, 5.0 mg, or any of the above doses ± 25%. In some such embodiments, the phosphodiesterase type 5 inhibitor is vardenafil.

[0038] In some embodiments, the inhaled dose of the type 5 phosphodiesterase inhibitor composition may be at least about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, or 1.6 mg. 1.7mg, 1.8mg, 1.9mg, 2mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3mg, 3.1mg, 3.2mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, or 5mg. In some embodiments, the inhaled dose of the type 5 phosphodiesterase inhibitor composition may not exceed about 0.1 mg, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1. Doses may be 6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, or 5 mg. In some embodiments, the daily dose of the inhaled phosphodiesterase type 5 inhibitor composition may be 0.25-1 mg, 0.1-4 mg, 0.1-2 mg, 1-4 mg, or doses within ±25% of these dose ranges. In some such embodiments, the phosphodiesterase type 5 inhibitor is vardenafil.

[0039] In some embodiments, the inhaled dose of the type 5 phosphodiesterase inhibitor composition may be at least about 0.001 mg, 0.0025 mg, 0.005 mg, 0.0075 mg, 0.01 mg, 0.0125 mg, 0.015 mg, 0.0175 mg, 0.02 mg, 0.025 mg, 0.0275 mg, 0.03 mg, 0.0325 mg, 0.035 mg, 0.0375 mg, 0.04 mg, 0.0425 mg, 0.05 mg, 0.0525 mg, 0.055 mg, 0.0575 mg, 0.06 mg, 0.0625 mg, 0.065 mg, or 0.0675 mg. The dosages are 0.07 mg, 0.0725 mg, 0.075 mg, 0.0775 mg, 0.08 mg, 0.0825 mg, 0.085 mg, 0.0875 mg, 0.09 mg, 0.0925 mg, 0.095 mg, 0.0975 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.225 mg, 0.25 mg, 0.275 mg, 0.3 mg, 0.325 mg, 0.35 mg, 0.375 mg, 0.4 mg, 0.425 mg, 0.45 mg, 0.475 mg, 0.5 mg, or any of the above doses ± 25%. In some such embodiments, the phosphodiesterase type 5 inhibitor is vardenafil.

[0040] In some embodiments, the inhaled dose of the type 5 phosphodiesterase inhibitor composition may not exceed about 0.001 mg, 0.0025 mg, 0.005 mg, 0.0075 mg, 0.01 mg, 0.0125 mg, 0.015 mg, 0.0175 mg, 0.02 mg, 0.025 mg, 0.0275 mg, 0.03 mg, 0.0325 mg, 0.035 mg, 0.0375 mg, 0.04 mg, 0.0425 mg, 0.05 mg, 0.0525 mg, 0.055 mg, 0.0575 mg, 0.06 mg, 0.0625 mg, 0.065 mg, or 0.0675 mg. 0.07mg, 0.0725mg, 0.075mg, 0.0775mg, 0.08mg, 0.0825mg, 0.085mg, 0.0875mg, 0.09mg, 0.0925mg, 0.095mg, 0.0975mg, 0.1mg, 0.125mg, 0.15mg, 0.175mg, 0.2mg, 0.225mg, 0.25mg, 0.275mg, 0.3mg, 0.325mg, 0.35mg, 0.375mg, 0.4mg, 0.425mg, 0.45mg, 0.475mg, 0.5mg, or any of the above doses ± 25%. In some embodiments, the daily inhaled dose for the subject may be 0.003-1 mg, 0.015-0.75 mg, 0.075-0.375 mg, 0.075-0.75 mg, or a dose within ±25% of these dose ranges. In some such embodiments, the phosphodiesterase type 5 inhibitor is vardenafil.

[0041] The terms “nominal dose” or “total dose” refer to the total amount of active agent packaged or dispensed for administration to a subject. For example, nominal dose refers to the total amount of active agent encapsulated in an inhaler capsule. Example 1

[0042] RT234 is a drug / device combination product (developed by Respira Therapeutics, Palo Alto, California, USA) that delivers the phosphodiesterase type 5 inhibitor vardenafil to the lungs via inhalation and has been shown to reduce pulmonary vascular resistance (PVR) in patients with pulmonary hypertension. This example describes a study designed to evaluate whether RT234 can improve oxygen uptake during cardiopulmonary exercise testing (CPET) in patients with pulmonary hypertension.

[0043] This prospective, multicenter, open-label, dual-cohort, dose-escalation phase IIb clinical trial will evaluate the safety and efficacy of RT234 in improving exercise parameters in patients with pulmonary hypertension (PH). Eligible patients must be diagnosed with PH by right heart catheterization (RHC), have a 6-minute walk distance ≥150 m, a minute ventilation / carbon dioxide production (VE / VCO2) slope ≥36, and be receiving no more than three stable oral and / or inhaled (non-parenteral) PH-specific baseline therapies. The expected sample size is 86 patients, who will be randomly assigned to two dose cohorts. Cohort 1 will receive 0.5 mg RT234, and Cohort 2 will receive 1.0 mg RT234. Each cohort will be further subdivided into two subgroups based on the number of medications used in the PH background (≤2 vs 3). The trial will evaluate changes in peak oxygen uptake (VO2) relative to baseline, changes in 6-minute walk distance, and the pharmacokinetic characteristics and safety of a single dose of RT234 30 minutes after a single administration of 0.5 mg or 1.0 mg RT234.

[0044] Patients must meet the following criteria to be eligible for enrollment: age 18-80 years (inclusive); diagnosed with pulmonary hypertension by right heart catheterization (RHC) and meeting any of the following classifications: (1) idiopathic, primary, or hereditary pulmonary hypertension; or (2) connective tissue disease-related pulmonary hypertension; or (3) pulmonary hypertension meeting the following criteria: human immunodeficiency virus (HIV) infection; ≥1 year after congenital systemic-pulmonary shunt surgery; history of drug / chemical exposure; and chronic thromboembolic pulmonary hypertension must be excluded by ventilation / perfusion scan, CT angiography, or pulmonary angiography; previous diagnosis of pulmonary hypertension must meet the following criteria: (1) no baseline pulmonary hypertension for ≥3 months prior to cardiopulmonary exercise test. The treatment regimen was significantly adjusted; (2) If glucocorticoids were used, the daily dose of prednisone (or other glucocorticoid equivalent dose) was ≤20mg for ≥30 days prior to the baseline cardiopulmonary exercise test; The pulmonary function test (PFT) within 6 months prior to the start of screening or during the screening period must meet the following criteria: (1) Forced expiratory volume in one second (FEV1) ≥60% of predicted value; (2) Forced vital capacity (FVC) ≥60% of predicted value; (3) Forced expiratory volume in one second / forced vital capacity ≥60%; The results of right heart catheterization before screening meet the diagnostic criteria for pulmonary hypertension: (1) Resting mPAP ≥20mmHg; (2) Pulmonary vascular resistance ≥300 to <500 dyn·s / cm -5 Pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤12 mmHg; pulmonary vascular resistance ≥500 dyn·s / cm -5Pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤15 mmHg (if pulmonary capillary wedge pressure data is unavailable, then left atrial mean pressure (mLAP) or left ventricular end-diastolic pressure ≤15 mmHg or ≤12 mmHg in the absence of left atrial obstruction); pulmonary vascular resistance >3 Wood units or >240 dyn·s / cm -5 World Health Organization / New York Heart Association functional class II-IV; Body mass index ≤35.9 kg / m² 2 Patients must have received at least 3 oral / inhaled pulmonary hypertension baseline therapies and have a stable regimen; a 6-minute walk distance ≥150m; a minute ventilation (VE) / volume carbon dioxide (VCO2) slope ≥36 in the baseline cardiopulmonary exercise test; and a peak respiratory exchange ratio (RER) ≥1.0 in the baseline cardiopulmonary exercise test. If the patient is using any of the following concomitant medications that may affect pulmonary hypertension, they must maintain a stable treatment dose for ≥1 month prior to screening and maintain the same dose throughout the study: (1) vasodilators; (2) digoxin; (3) L-arginine supplements; (4) anticoagulants (maintaining / stabilizing anticoagulation within the therapeutic range for ≥1 month prior to screening). “Stable” is defined as: no change in the pulmonary hypertension-specific drug treatment regimen from 3 months prior to screening visit 1 to the study period, and no adjustment of the pulmonary hypertension-specific drug dose within 1 month prior to screening. Body mass index ≥36.0 kg / m² 2 Individuals who meet the criteria may be considered for enrollment in the trial.

[0045] Patients meeting any of the following criteria will be excluded: baseline generalized hypotension (mean arterial pressure <50 mmHg or systolic blood pressure (SBP) <90 mmHg at screening); history of uncontrolled hypertension (systolic blood pressure >175 mmHg or sitting diastolic blood pressure >110 mmHg); history of chronic uncontrolled asthma; inability or difficulty using an inhaler; intravenous administration of positive inotropic agents within 30 days prior to baseline cardiopulmonary exercise testing; use of parenteral pulmonary hypertension medications; use of riociguat as basic therapy for pulmonary hypertension ≤1 month prior to screening initiation or during the study period up to the end of visit 4; use of oral / topical / inhaled nitrates within 2 weeks prior to baseline cardiopulmonary exercise testing; portal pulmonary hypertension, portal hypertension, or Child-Pugh syndrome. Grade B or C chronic liver disease; history of atrial septal septum stomata; known uncorrected right-to-left shunt; clinically significant persistent patent foramen ovale; known Eisenmenger syndrome; paroxysmal or uncontrolled atrial fibrillation; chronic renal insufficiency; alanine aminotransferase or aspartate aminotransferase ≥ 3 times the upper limit of normal; platelet count < 50,000 / μL at screening. -1 Hemoglobin concentration <9g / dL during screening -1 Evidence or history of left ventricular disease and / or clinically significant heart disease.

[0046] After confirmation of eligibility for inclusion, the study will commence with a screening visit (Visit 1), which must be completed 3 to 28 days prior to the baseline cardiopulmonary exercise test visit (Figure 2). The screening visit includes two 6-minute walk tests (6MWTs), with at least a 2-day interval between the two tests; if well tolerated by the patient, they can be performed on the same day with at least a 2-hour interval (this aims to eliminate the learning effect of the 6-minute walk test, and the relative difference between the two measurements must be ≤15%). The average of the two 6-minute walk distances during the screening period will be used as the baseline 6-minute walk distance. If the relative difference between the two measurements is >15%, a third 6-minute walk test may be performed. If a third 6-minute walk test is performed, the average of the two longest 6-minute walk test results will be used as the baseline 6-minute walk distance. Urine or serum pregnancy tests may be performed concurrently during Screening Visit 1. Patient height data may also be collected during Screening Visit 1.

[0047] At the baseline cardiopulmonary exercise test visit (Visit 2; Day 1), enrolled patients are required to return to the testing center to complete: pre-test assessment, baseline cardiopulmonary exercise test to measure peak oxygen uptake (VO2), and post-test assessment. Eligible patients whose baseline data are deemed valid by the cardiopulmonary exercise test core laboratory will enter the treatment phase (Visits 3 and 4), receiving RT234 and undergoing a post-administration cardiopulmonary exercise test and a 6-minute walk test. For patients taking oral vitamin K antagonists, the international normalized ratio of prothrombin time can be measured concurrently.

[0048] At the treatment visit for cardiopulmonary exercise testing (Visit 3; Day 8), patients must return to the testing facility to complete: pre-test assessment and a single inhalation of RT234 (0.5 mg for Cohort 1, 1.0 mg for Cohort 2) with the assistance of the research team. Cardiopulmonary exercise testing will be performed 30 minutes after administration (time points at each visit should be relatively consistent throughout the day, with an error not exceeding 2 hours), followed by post-test assessment. The primary endpoint may be the change in peak oxygen uptake from Day 1 to Day 8 (30 minutes after administration). Urine or serum pregnancy tests can be performed concurrently during Visit 3.

[0049] During the 6-minute walk test treatment visit (Visit 4; Day 15), the patient will undergo pre-test assessment and a single inhalation of RT234. The 6-minute walk test will be performed 30 minutes after administration, followed by a post-test assessment. Plasma samples for pharmacokinetic analysis should be collected before and after RT234 administration during Visits 3 and 4. Urine or serum pregnancy tests may be performed concurrently during Visit 4.

[0050] RT234 was administered to patients only during visits 3 and 4 (Figure 1); patients should not use RT234 outside of these two visits. After all tests were completed at visits 3 and 4, patients were required to remain under observation for 4 hours for pharmacokinetic sampling and safety monitoring, which continued for up to 30 days after visit 4. A safety follow-up telephone assessment was conducted at visit 5 (day 45 ± 3 days).

[0051] Statistical analysis estimated the total sample size at 86 enrolled patients. With a 5% dropout rate, the calculated sample sizes for each dose cohort (0.5 mg and 1.0 mg) were 17 and 26 patients respectively, who used a maximum of two and three background medications. These sample sizes were calculated using a one-sample two-sided t-test (significance level 0.05, power 80%) to test the null hypothesis that "peak oxygen uptake in a cardiopulmonary exercise test performed 30 minutes after RT234 administration remains unchanged from baseline to post-administration." The mean change in baseline for patients using a maximum of two and three background medications in each dose cohort was assumed to be 1.5 mL O2·kg⁻¹. –1 ·min –1 and 1.2 mL O2·kg –1 ·min –1 The standard deviation was assumed to be 2 mL O2·kg for each dose cohort and background medication group. –1 ·min –1 .

[0052] The primary efficacy analysis will be conducted based on a modified intention-to-treat (mITT) analysis set, which includes all patients who received treatment and have baseline and post-baseline peak oxygen uptake (POU) assessment data. This modified MITT analysis set will serve as the basis for all efficacy analyses. For patients in the protocol analysis set (modified MITT patients without any significant protocol deviations), a repeated analysis procedure using a one-sample t-test (if POU follows a normal distribution) will be employed to test the two-sided null hypothesis (significance level 0.05) that there has been no change in POU. If the normality hypothesis is not rejected, the 95% confidence interval for the change in the mean POU will be calculated using a t-test. If the normality hypothesis is rejected, a one-sample Wilcoxon signed-rank test will be used to determine the median change in POU and its estimated 95% confidence interval.

[0053] Secondary efficacy analyses will be performed on the modified intention-to-treat analysis set and repeated on the conformity analysis set as described in the primary efficacy analysis.

[0054] The pharmacokinetic parameters of vardenafil will also be determined, and the correlation between vardenafil exposure and changes in cardiopulmonary exercise test parameters and 6-minute walk distance will be analyzed. Plasma samples will be collected at the following time points: before administration of RT234 at visits 3 and 4; 3, 15, and 30 minutes after administration; at the end of the exercise cycle; and 45, 75, 120, 180, and 240 minutes after administration. The concentration of vardenafil in the pharmacokinetic samples will be determined according to the aforementioned method. Pharmacokinetic parameter estimation parameters include: T... max C max The area under the curve (AUC) from 0 to the last measurable concentration. 0–Last The area under the curve from 0 to infinity (AUC) 0–Inf and half-life (t) 1 / 2 For cardiopulmonary exercise testing, exposure-response analysis will be based on AUC0. –Last The baseline change in peak oxygen uptake measured 30 minutes after RT234 administration; for the 6-minute walk test, exposure-response analysis will be based on AUC0. –Last Changes in 6-minute walking distance from baseline (mean 6-minute walking distance during the screening period) to 6-minute walking distance 30 minutes after RT234 administration.

[0055] The standard linear trapezoidal method will be used to calculate all available drug concentration measurements to derive pre-defined pharmacokinetic parameters (T0) for treated patients with available pharmacokinetic measurement data. max C max AUC 0–Last AUC 0–Inf and t 1 / 2 Pharmacokinetic parameters will be summarized using standard descriptive statistics (mean, median, number of cases, standard deviation, minimum, maximum, and coefficient of variation), and 90% confidence intervals will be provided as appropriate.

[0056] The primary efficacy endpoint was the change in peak oxygen uptake (VO2) from baseline during a cardiopulmonary exercise test performed 30 minutes after a single inhalation of 0.5 mg or 1.0 mg RT234. Secondary efficacy endpoints included: changes in 6-minute walk distance from baseline (mean of two 6-minute walk distances during the screening period) to measurements 30 minutes after RT234 administration; changes in minute ventilation / carbon dioxide production slope during cardiopulmonary exercise testing from baseline to post-administration; changes in peak end-tidal carbon dioxide partial pressure response to exercise (i.e., the highest level during cardiopulmonary exercise testing) from baseline to post-administration; changes in exercise duration during cardiopulmonary exercise testing from baseline to post-administration; changes in peak perceived dyspnea during cardiopulmonary exercise testing as assessed by the Modified Burger Dyspnea Scale (MDDS) from baseline to post-administration; changes in Patient Global Impression Severity Score (PGI-S) for cardiopulmonary exercise testing from baseline to post-administration (assessed before cardiopulmonary exercise testing, 2 minutes after treadmill exercise with a mask on, and every 5 minutes after mask removal [at minutes 7, 12, and 17]); and changes in the Patient Global Impression Severity Score for the 6-minute walk test from the screening period to post-administration (assessed before the 6-minute walk test and 2 minutes after completion of the test).

[0057] Exploratory endpoints may include, but are not limited to: the proportion of patients whose minute ventilation / carbon dioxide production slope in the cardiopulmonary exercise test improved from baseline to post-administration, according to the standard risk stratification (low, intermediate, high), and the following additional cardiopulmonary exercise test parameters from baseline to post-administration: exercise ECG response, oxygen uptake at the ventilation threshold, change in respiratory exchange ratio at peak oxygen uptake, exercise systolic blood pressure response, exercise pulse oximetry response, modified Burger Dyspnea Scale score during non-peak periods of the entire exercise test (every minute during non-peak periods of the cardiopulmonary exercise test and 6 minutes after the test), Burger Subjective Perceived Fatigue Assessment score during the entire exercise test (every 2 minutes during the cardiopulmonary exercise test and 6 minutes after the test), Duke Activity Status Index (which may be measured 10 minutes after the cardiopulmonary exercise test), and four-point angina scale (every 2 minutes during the cardiopulmonary exercise test and 6 minutes after the test, or as indicated until symptoms resolve).

[0058] Safety assessment will include the characterization of adverse events and evaluation of acute physical and cardiac symptoms for a single dose (0.5 mg or 1.0 mg) of RT234. The incidence and severity of adverse events occurring during treatment will be summarized according to the following categories: the current version of the Dictionary of Regulatory Activities for Organ System Classification and Preferred Terminology, the current version of the National Cancer Institute's General Terminology Standard for Adverse Events (GTAS), and causality (attributable to the study treatment and related / unrelated to the investigational drug). Vital signs (blood pressure [BP], heart rate, respiratory rate, body temperature, and pulse oxygen saturation) will be monitored, and changes from baseline to post-dose will be measured via physical examination and a 12-lead electrocardiogram (ECG). Interval medical history will be recorded for any signs, symptoms, or events that have occurred since the last study visit. Vital signs may be assessed after 5 minutes at rest (sitting). Vital sign measurements should be performed before any blood collection procedures. Vital signs may also be monitored during and after the cardiopulmonary exercise test. Heart rate may be measured via continuous ECG monitoring during and 6 minutes after the cardiopulmonary exercise test. Blood pressure can be measured every 2 minutes during cardiopulmonary exercise testing and 6 minutes after the test. Pulse oxygen saturation can be measured every minute during cardiopulmonary exercise testing and 6 minutes after the test. Vital signs can also be measured at visit 4 during the 6-minute walk test during the treatment period (before RT234 administration; 5 and 15 minutes after administration, i.e., before the 30-minute 6-minute walk test; and 60 and 120 minutes after administration). Example 2

[0059] This embodiment describes a study aimed at evaluating whether RT234 can improve oxygen uptake during cardiopulmonary exercise testing (CPET) in patients with pulmonary hypertension. The only difference between this embodiment and Example 1 is that the study plans to include 37 patients as the estimated sample size, divided into three dose cohorts. Cohort 1 is expected to consist of 7 patients receiving 0.5 mg RT234; Cohort 2 is expected to consist of 15 patients receiving 1.0 mg RT234; and Cohort 3 is expected to consist of 15 patients receiving 2.0 mg RT234. Furthermore, patients with a baseline peak oxygen uptake >15 mL / mg / kg will be excluded. In all other important respects, the study described in this embodiment will be similar to the study in Example 1.

Claims

1. A method for treating pulmonary hypertension, the method comprising administering to a subject in need an effective amount of vardenafil or a pharmaceutically acceptable saline or hydrate thereof, The vardenafil is administered via on-demand inhalation using a portable inhaler, and The vardenafil mentioned above should be administered at least 2-30 minutes before physical activity.

2. The method as described in claim 1, characterized in that, Administration of the vardenafil involves targeted delivery of vardenafil to the small airways of the subject's lungs.

3. The method as described in claim 2, characterized in that, The nominal dose of vardenafil delivered to subjects upon inhalation is approximately 0.5 mg to 1.0 mg.

4. The method as described in claim 3, characterized in that, The nominal dose of vardenafil delivered to the subject upon inhalation is approximately 0.5 mg.

5. The method as described in claim 3, characterized in that, The nominal dose of vardenafil delivered to the subject upon inhalation is approximately 1.0 mg.

6. The method as described in claim 2, characterized in that, The nominal dose of vardenafil delivered to subjects upon inhalation is approximately 0.5 mg to 2.0 mg.

7. The method as described in claim 6, characterized in that, The nominal dose of vardenafil delivered to the subject upon inhalation is approximately 2.0 mg.