Inhaled iloprost for rescue therapy and as needed treatment in pulmonary hypertension

Abstract

A method for treating pulmonary hypertension is provided. The method comprises administering an effective amount of iloprost to a subject as on-demand or rescue medication (also called prorenata, PRN), where iloprost is administered to the patient by inhalation using a portable soft mist inhaler. In a preferred embodiment, the soft mist inhaler is a Respimat™ or Medspray™ wet aerosol inhaler. A method for treating a patient suffering from pulmonary hypertension, comprising: (a) providing a portable, pre-filled soft mist inhaler adapted to deliver an effective amount of iloprost; and (b) administering the effective amount of iloprost to the patient by inhalation on demand.

Description

Detailed Description of the Invention

[0001] [Technical Field] The present invention relates to methods and compositions for the treatment of patients by iloprost aerosol therapy.

[0002] [Background of the Invention] Iloprost is a synthetic prostacyclin analogue that is known to have vasodilating, fibroblast growth inhibitory, platelet aggregation reducing, and anti-inflammatory and antimitogenic properties, which are responsible for the biological activity of prostacyclin (also called PGI2 or epoprostenol). According to IUPAC, the chemical name of iloprost is 5-{(E)-(1S,5S,6R,7R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]-bicyclo[3.3.0]octane-3-ylidene}pentanoic acid. Iloprost is approved for the treatment of pulmonary (arterial) hypertension, scleroderma, Raynaud's phenomenon and certain types of ischemia. Iloprost is available as an aqueous solution in various concentrations (10 μg / ml to 100 μg / ml) in glass ampoules, which further contain tromethamine, 96% ethanol, sodium chloride, hydrochloric acid (for pH adjustment) and water for injection. For the treatment of pulmonary hypertension, iloprost is commercially available as Ventavis (trademark) at two concentrations of 10 μg / ml (Ventavis-10) and 20 μg / ml (Ventavis-20).

[0003] Pulmonary hypertension (PH) is a serious and potentially life-threatening disease defined by an elevated mean pulmonary artery pressure of more than 25 mmHg. Common signs and symptoms of pulmonary hypertension include shortness of breath (dyspnea), exercise intolerance, fatigue, dizziness or syncope, chest tightness or pain, edema, cyanosis, tachycardia, and palpitations. Pulmonary hypertension is currently classified by the WHO into five groups: Group 1: Pulmonary arterial hypertension (PAH), Group 2: Pulmonary hypertension due to left heart disease, Group 3: Pulmonary hypertension due to lung disease and / or hypoxia, Group 4: Pulmonary hypertension due to pulmonary artery occlusion, and Group 5: Pulmonary hypertension with unknown mechanisms and / or multifactorial mechanisms. The deciphering of the pathophysiological background of PH has facilitated the development of drug therapies specifically for PH, particularly Groups 1 and 4, over the past several decades. Currently, several PH-specific drug therapies are available that address three major signaling pathways of pulmonary vasomodulation. These include epoprostenol (intravenous), iloprost (inhaled, intravenous), treprostinil (inhaled, intravenous, subcutaneous, oral), beraprost (oral), and selexipag (oral) which address the prostacyclin pathway; sildenafil (oral), tadalafil (oral), vardenafil (oral), and riociguat (oral) which address the nitric oxide pathway; and bosentan (oral), ambrisentan (oral), and macitentan (oral) which address the endothelin pathway. These drugs primarily work through vasodilatory effects and have significantly improved the treatment of P(A)H, including improving clinical symptoms, slowing disease progression, and extending survival time. However, despite these advances, there is still no cure for the disease. Patients often report suffering from disabling symptoms even when treated with one or more PH-specific maintenance therapies. PH continues to significantly impair patients' quality of life and frequently hinders their participation in social and professional life. Daily activities become burdensome, exercise capacity varies from day to day and hour to hour, and some patients experience pulmonary hypertension attacks during exercise or when the effects of medication subside.These symptoms are often accompanied by anxiety and mental health problems, and patients tend to avoid being alone or engaging in physical activity.

[0004] Inhaled iloprost is approved in many countries for aerosol therapy of pulmonary (arterial) hypertension (P(A)H), either as monotherapy or in addition to existing pharmacotherapy specifically for pulmonary (arterial) hypertension, such as bosentan, to improve exercise capacity and symptoms. Inhaled iloprost (Ventavis®, Bayer Vital GmbH, Actelion Pharmaceutical, Janssen) is marketed in two strengths (Ventavis-10, Ventavis-20) and is administered 6 to 9 times per day using a Breelib® nebulizer, I-Neb® AAD® inhalation system, or Venta-Neb® nebulizer. The target dose of Ventavis® therapy is 2.5 μg or 5 μg of iloprost delivered to the nebulizer mouthpiece, but this varies depending on patient tolerance. Depending on individual needs and tolerance, a dose of 2.5 μg or 5 g per inhalation session may be administered 6 to 9 times per day. Breelib® is a handheld, battery-powered, breath-activated vibrating mesh inhalation system. When Ventavis-10 (1 ml ampoule) or Ventavis-20 (1 ml ampoule) is filled into the device's drug chamber, 2.5 μg or 5 μg of iloprost, respectively, is delivered to the mouthpiece. The duration of an inhalation session with a Breelib® nebulizer is approximately 3 minutes, depending on the breathing pattern of the inhaling patient. The I-Neb® AAD® system is a portable, handheld vibrating mesh technology nebulizer that monitors the breathing pattern to determine the aerosol pulse time required to deliver a preset dose of 2.5 μg or 5 μg. This device can be used to administer Ventavis-10 or Ventavis-20 (each in a 1 ml ampoule), and the amount delivered is controlled by the drug chamber in combination with a control disk. Ventavis-10 is used routinely, delivering 2.5 μg or 5.0 μg of iloprost to the nebulizer mouthpiece within 3.2 minutes or 6.5 minutes, respectively. Only patients who maintain a 5 μg dose and repeatedly experience prolonged inhalation time with Ventavis-10 are considered suitable for switching to Ventavis-20.Venta-Neb® is a portable, ultrasonic, battery-powered nebulizer that guides the inhalation patient using optical and acoustic signals. Each inhalation session with Venta-Neb® delivers the contents of one 2ml ampoule of Ventavis-10 to the nebulizer's drug chamber immediately before use. Two programs are available: Program 1 delivers 5μg of iloprost to the mouthpiece within 25 inhalation cycles, while Program 2 delivers 2.5μg of iloprost within 10 inhalation cycles.

[0005] According to the product information in the European Public Assessment Report (EPAR), the dosage and administration of Ventavis® include the administration of inhaled iloprost according to individual needs and tolerance. Therefore, contrary to the claims of Weers et al. in the US10,912,778B2 patent ("Method for the Treatment of Pulmonary Hypertension"), the use of inhaled iloprost as needed (also known as pro re nata, meaning when the need arises or is directed to do so) is foreseeable and specified in the drug labeling. While PRN use of Ventavis® is theoretically possible with the available inhalation systems (Breelib®, I-Neb®, AAD®, and Venta-Neb®), it is cumbersome. There are several requirements for pharmacotherapy with PRN for PH. Firstly, the pharmacodynamics and pharmacokinetics of drugs used in PRNs must enable rapid onset of action (within minutes) after administration and provide pulmonary selectivity to avoid potential side effects in the systemic circulation. Secondly, the method and manner of drug administration must be convenient, easy to use, portable, and safe. In the case of inhaled iloprost, the pharmacodynamics and pharmacokinetics suitable for PRN use are widely documented, for example, Gessler et al. (Pulm Circ. 2017, 7(2):505-513, “The safety and pharmacokinetics of rapid Iloprost aerosol delivery via the BREELIB nebulizer in pulmonary arterial hypertension”) and Olschewski et al. (Chest 2003; 124(4):1294-1304, “Pharmacodynamics and pharmacokinetics of inhaled Iloprost, aerosolized by three different devices, in severe pulmonary hypertension”).The three nebulizers recommended for aerosol administration of Ventavis® are portable, but they do not facilitate the pre-regulation (PRN) use of the medication. Each treatment session requires several different procedures for preparing and performing inhalation. These include loading a separate Ventavis® ampoule into a device that is not pocket-sized, preparing the device, opening a single glass ampoule of Ventavis®, transferring the medication to the device's drug chamber using a pipette or syringe, inhalation for at least 3 minutes, removing residual medication, and cleaning the device.

[0006] The EP000002701683B1 patent, “Iloprost administration as an aerosol bolus,” provided the basis for the development of the Breelib® nebulizer for Ventavis® aerosol therapy. The aforementioned patent focuses on a vibrating mesh nebulizer capable of delivering iloprost in two minutes or less. While the use of soft mist inhalers is mentioned in general terms, no detailed description of how such soft mist inhalers would be used for iloprost inhalation therapy is disclosed. The US10,912,778B2 patent, “Method for treating pulmonary hypertension,” focuses on an inhaled formulation of a phosphodiesterase-5 inhibitor and claims “a method for treating pulmonary hypertension comprising administering an effective amount of a vasodilator to a subject in need thereof, wherein the vasodilator is administered by Prorenata inhalation using a portable inhaler.” The aforementioned patent mentions iloprost as a possible vasodilator and various soft mist inhalers as possible devices, but does not disclose a detailed description of how iloprost is used in iloprost PRN therapy with such soft mist inhalers. Furthermore, the prolenata use of iloprost has already been foreseen and disclosed in prior art and prior publications (see, for example, the product information in the European Publicly Available Medicinal Products Review Report (EPAR) available at https: / / www.ema.europa.eu / en / medicines / human / EPAR / ventavis).

[0007] To date, in contrast to the treatment options for asthma and COPD, there are no specific PRN therapies available for pulmonary hypertension. For example, palliative care is an essential category of asthma treatment and is provided to all asthma patients for as-needed relief of sudden symptoms, such as during asthma exacerbations or flares, or for short-term prevention of exercise-induced asthma. A specific type of PRN therapy in asthma is a maintenance and palliative care plan, also known as "MART" or "SMART" therapy, in which the patient receives inhaled corticosteroid formoterol as maintenance therapy twice or once daily on a regular basis, with additional doses taken with the same inhaler for symptom relief.

[0008] The object of the present invention is to provide a method and composition for administering iloprost that can be inhaled as PRN therapy, overcoming at least one of the drawbacks and weaknesses known of conventional iloprost aerosol therapy.

[0009] [Overview of the prefecture] This specification provides a method and composition for treating pulmonary hypertension by inhaling, as needed, an effective amount of iloprost, also known as prorenata, using a portable, pre-filled soft mist inhaler. In preferred embodiments, the soft mist inhaler is a Respimat® or Medspray® wet aerosol inhaler.

[0010] Inhaled iloprost is approved in many countries as Ventavis® for the treatment of pulmonary (arterial) hypertension. This prostacyclin analog is administered regularly 6 to 9 times a day using various nebulizers. The recommended nebulizers do not facilitate the use of PRN inhaled iloprost, and its handling is cumbersome. The present invention provides PRN inhaled iloprost for the acute treatment of PH as needed, in patients with no prior treatment history or those regularly treated with one or more PH-specific medications, to promote improved exercise tolerance and daily living activities, alleviate disease symptoms, or overcome acute pulmonary hypertension attacks. In a preferred embodiment, PRN iloprost is administered in a portable, pre-filled soft mist inhaler such as Respimat® or Medspray®, allowing the patient to inhale an effective dose of up to 5 μg of iloprost anytime, anywhere.

[0011] Further aspects and embodiments will be revealed based on the following detailed description, examples, and claims. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 shows the mean pulmonary arterial pressure (PAP) after inhalation of iloprost 2.5 mg or 5 μg in patients with pulmonary arterial hypertension (0 min: baseline before inhalation); n=4; mean ± SEM; *p<0.05, Mann-Whitney rank-sum test. [Figure 2] Figure 2 shows pulmonary vascular resistance (PVP) after inhalation of iloprost 2.5 mg or 5 μg in patients with pulmonary arterial hypertension (0 min: baseline before inhalation); n=4; mean ± SEM; *p<0.05, Mann-Whitney rank-sum test. [Figure 3]Figure 3 shows the mean systemic arterial pressure (SAP) after inhalation of iloprost 2.5 mg or 5 μg in patients with pulmonary hypertension (0 min: baseline before inhalation); n=4; mean ± SEM; ns: no significant difference, Mann-Whitney rank-sum test. [Figure 4] Figure 4 shows systemic vascular resistance (SVR) after inhalation of iloprost 2.5 mg or 5 μg in patients with pulmonary hypertension (0 min: baseline before inhalation); n=4; mean ± SEM; ns: no significant difference, Mann-Whitney rank-sum test. [Modes for carrying out the invention]

[0013] [Detailed description of the invention] The present invention provides a method and composition for administering iloprost by a pre-filled, portable, and easy-to-use soft mist inhaler as prorenata (PRN, on-demand drug therapy or rescue drug therapy, meaning when a situation occurs or is directed to occur) therapy for pulmonary hypertension.

[0014] Iloprost is also known by its IUPAC chemical name 5-{(E)-(1S,5S,6R,7R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]-bicyclo[3.3.0]octane-3-ylidene}pentanoic acid. Iloprost solution is commercially available as Ventavis® for aerosol therapy of pulmonary hypertension. Ventavis® solution contains iloprost along with trometamol, 96% ethanol, sodium chloride, hydrochloric acid (for pH adjustment), and sterile water for injection in a 1 or 2 ml glass ampoule. Currently, Ventavis® is available in two strengths, containing either 10 μg / ml iloprost (Ventavis-10) or 20 μg / ml iloprost (Ventavis-20). Furthermore, in some countries, an aqueous iloprost formulation (Ilomedin®) with an iloprost concentration of 100 μg / ml is available for intravenous administration for the treatment of several peripheral artery diseases, which also contains trometamol, 96% (v / v) ethanol, sodium chloride, hydrochloric acid (1N), and sterile water for injection as excipients.

[0015] Ventavis® is approved in many countries for aerosol therapy of pulmonary (arterial) hypertension (P(A)H), either as monotherapy or as an addition to existing drug therapies specifically for P(A)H, such as bosentan, to improve exercise capacity and symptoms. Ventavis® solution is aerosolized and delivered to patients by inhalation using various nebulizers. According to the latest product information, Breelib®, I-Neb®, AAD® inhalation systems, or Venta-Neb® nebulizers are recommended as suitable devices for the use of Ventavis® by inhalation. These devices are typical nebulizers that require multiple steps to perform the inhalation procedure. The procedure involves opening a glass ampoule containing 1 or 2 ml of Ventavis®, assembling the nebulizer, transferring the Ventavis® solution to the nebulizer's spray chamber using a pipette or syringe, inhaling for at least 3 minutes to deliver a nominal dose of 2.5 or 5.0 μg of iloprost to the mouthpiece, removing any residual solution from the spray chamber, and cleaning the various parts of the nebulizer. In principle, the recommended nebulizer can be used regardless of the main power supply. As foreseen in the product information in the European Publicly Released Medical Products Review Report (EPAR), PRN use is theoretically possible but cumbersome.

[0016] The use of soft mist inhalers in iloprost aerosol therapy has been suggested several times in the past. However, data and specific methods for using such devices in iloprost aerosol therapy are not available.

[0017] An important feature of the present invention is the selection of a soft mist inhaler (SMI) for administering iloprost as prolenata therapy for pulmonary hypertension. In a preferred embodiment, the soft mist inhaler is a Respimat® (Boehringer Ingelheim, Germany), and in a more preferred embodiment, the soft mist inhaler is a Medspray® wet aerosol inhaler (Medspray, The Netherlands).

[0018] The Respimat® soft mist inhaler is a handheld, pocket-sized device that produces an inhalable aerosol with a slow, long-lasting mist. By using mechanical force to force an unpressurized drug solution through a two-channel nozzle (Unibloc), the drug solution is accelerated and split into two converging jets that collide at a specific angle, breaking the drug solution into inhalable droplets. The mechanical energy for the aerosolization process is provided by rotating the bottom of the device 180 degrees to increase the tension of a spring around a flexible drug solution container. When activated by the patient, the energy from the spring is released, pressurizing the flexible container holding the liquid formulation, thereby pushing a measured amount of liquid through the two nozzles and dispersing it into an inhalable aerosol. Respimat® is already commercially available and can be used, for example, for aerosol administration of tiotropium in COPD.

[0019] The Medspray® wet aerosol inhaler is a handheld, preservative-free, non-pressurized metering device that includes a microfabricated nozzle manufactured by wafer stepper lithography and etching technology. The aerosol is generated according to the Rayleigh splitting principle, with the liquid dispersed into droplets by mechanical means through a series of nozzles. The medication can be stored in a container with a mechanical pump system or in a pre-filled glass syringe already fitted with a soft mist nozzle. Various nozzles can be used to target specific areas of the airway. Mechanical energy for the aerosolization process is provided, for example, by a spring that is loaded and released by the patient.

[0020] For use in PRN iloprost aerosol therapy for pulmonary hypertension, the drug containers of Respimat® or Medspray® soft mist inhalers are pre-filled with Ventavis-10 or Ventavis-20, or 100 μg / ml Ilomedin®, or 100 μg / ml Ilomedin®, diluted with physiological saline to achieve an iloprost drug concentration in the range of 10 μg / ml to 100 μg / ml.

[0021] The following is a non-exclusive list of examples detailing and illustrating the use of soft mist inhalers for the independent administration of inhaled iloprost as PRN therapy for patients with PAH and other forms of PH.

[0022] [Example 1] Respimat (trademark) and Ventavis-20 The feasibility of delivering iloprost solution by Respimat® was evaluated in an in vitro spray test. The physical aerosol characteristics and output of Respimat® filled with placebo and Respimat® filled with Ventavis-20 were evaluated. To compare the particle size distributions of two different solutions, laser light scattering (Sympatec®, Clausthal-Zellerfeld, Germany) was used to determine the mass median aerodynamic diameter (MMAD) of the aerosol droplets. The measurements (performed 5 times with a duration of 1 second and a sampling rate of 50 milliseconds) were carried out without adding an air stream and with a distance of 5 cm between the mouthpiece and the laser beam. By analyzing the data in MIE mode and setting the density of the sprayed solution equal to the unit density, the measured volume median diameter (VMD) became equal to the mass median aerodynamic diameter. The fine particle fraction (FPF) was defined as the mass of particles with a size less than 5.25 μm in the total emitted dose divided by the total emitted dose of the aerosol particles. The geometric standard deviation (GSD) was calculated from the laser diffraction values according to the following formula:

[0023] [Number] <L To evaluate the amount of aerosol released by a single ejection from Respimat®, the weight of the drug container of the device was measured before and after a series of 40 consecutive ejections.

[0024] First, the parameters of Respimat® filled with placebo were evaluated. After the experiment with Respimat® filled with placebo, the drug container was completely emptied with a syringe. The weight of the drug container was measured, and 3.0 ml of Ventavis-20 was filled into the drug container with a syringe. Next, a second series of experiments was performed to obtain the aerosol parameters of Respimat® filled with Ventavis-20. The results are summarized in Table 1 below:

[0025]

Table 1

[0026]

Table 2

[0027] [Table 3] [Example 4] Medspray (trademark) wet aerosol inhaler and Ventavis-20 The feasibility of delivering iloprost solution using a Medspray® wet aerosol inhaler was evaluated in an in vitro spray test. The physical aerosol properties of Medspray® wet aerosol inhalers filled with either 0.9% sodium chloride or Ventavis-20 were evaluated. To compare the particle size distribution of the two different solutions, the aerodynamic median particle diameter (MMAD) of aerosol droplets was determined using laser light scattering (Sympatec®, Clausthal-Zellerfeld, Germany). Measurements (5 times with a duration of 1 second and a sampling rate of 50 milliseconds) were performed without adding airflow and with a distance of 5 cm between the mouthpiece and the laser beam. By analyzing the data in MIE mode and setting the density of the sprayed solution to equal the unit density, the measured volume-average diameter (VMD) was equal to the aerodynamic median particle diameter. The particulate fraction (FPF) was defined as the mass of particles smaller than 5.25 μm in the total emitted dose divided by the total emitted dose of aerosol particles. The geometric standard deviation (GSD) was calculated from the laser diffraction values ​​according to the following formula:

[0028]

number

[0029] [Table 4] [Example 5] Medspray® wet aerosol inhaler and 100 μg / ml Ilomedin® In this in vitro spray test, Medspray® wet aerosol inhalers filled with either 0.9% sodium chloride or 100 μg / ml Ilomedin® were compared. The physical aerosol properties were evaluated as described above (see Example 4). The results are summarized in Table 5.

[0030] [Table 5] [Example 6] Medspray® wet aerosol inhaler and 50 μg / ml Ilomedin® In this in vitro spray test, Medspray® wet aerosol inhalers were filled with either 1 ml of 0.9% sodium chloride or 1 ml of 50 μg / ml Ilomedin® (0.5 ml of 100 μg / ml Ilomedin® diluted with 0.5 ml of 0.9% NaCl). The physical aerosol properties were evaluated as described above (see Example 4). The results are summarized in Table 6.

[0031] [Table 6] [Example 7] Medspray® wet aerosol inhalers with smaller nozzle diameters (e.g., 1.5 or 1 μm) By changing the diameter of the spray nozzle hole, the resulting droplet size distribution can be adjusted to meet specific requirements for localized drug deposition in the airways. When an aqueous solution is pushed through the nozzle, a jet is generated, which automatically splits into droplets (Rayleigh splitting), with the droplet size theoretically being twice the hole size. When using a nozzle diameter of 1.5 or 1 μm, the droplet size range is within the range of 2 μm to 5.0 μm. In addition, the slow speed of the aerosol promotes aerosol deposition deep into the lungs. By implementing flow restriction during inhalation (e.g., with a valve) and slowing down the airflow during inhalation, peripheral deposition can be further increased.

[0032] The examples demonstrate that iloprost-containing aerosols suitable for deep lung deposition can be provided by using the Respimat® or Medspray® wet aerosol inhaler.

[0033] [dosage] This specification provides iloprost doses of 0.4 μm to 5 μg delivered in 1 to 10 puffs to the mouthpiece of a Respimat® or Medspray® wet aerosol inhaler in a single PRN inhalation treatment. Single doses of approximately 2.5 μg and approximately 5 μg are also preferred, as are currently used in the treatment of pulmonary arterial hypertension.

[0034] The following is a non-exhaustive list of possible combinations of iloprost drug concentrations and release amounts per puff that are suitable for delivering the required dose in a single PRN treatment session.

[0035] [Example 8] Respimat (trademark) and 100 μg / ml iloprost (Respimat100) Table 7 shows the amount of iloprost delivered through the mouthpiece of the Respimat® soft mist inhaler, according to the amount of aerosol released and the number of exhalations, when using an iloprost drug concentration of 100 μg / ml.

[0036] [Table 7] [Example 9] Respimat (trademark) and 20 μg / ml iloprost (Respimat20) Table 8 shows the amount of iloprost delivered through the mouthpiece of the Respimat® soft mist inhaler, according to the amount of aerosol released and the number of sprays, when using an iloprost drug concentration of 20 μg / ml.

[0037] [Table 8] Using iloprost drug concentrations in the range of 20 μg / ml to 100 μg / ml is within the scope of the present invention. In another preferred embodiment, the iloprost drug concentration is 50 μg / ml, and when the release volume per spray of Respimat (trademark) is set to 20 μl, the delivery dose is 1 μg with one spray, 2 μg with two sprays, 3 μg with three sprays, 4 μg with four sprays, and 5 μg with five sprays.

[0038] [Example 10] Medspray® wet aerosol inhaler and 100 or 50 μg / ml iloprost (Medspray 100 or 50) Table 9 shows the amount of iloprost delivered through the mouthpiece of the Medspray® soft mist inhaler, corresponding to the amount of aerosol released and the number of sprays, when using iloprost drug concentrations of 100 μg / ml or 50 μg / ml.

[0039] [Table 9] [Example 11] Medspray® wet aerosol inhaler and 20 μg / ml iloprost (Medspray20) Table 10 shows the amount of iloprost delivered through the mouthpiece of the Medspray® soft mist inhaler, according to the amount of aerosol released and the number of sprays, when using an iloprost drug concentration of 20 μg / ml.

[0040] [Table 10] Using iloprost drug concentrations in the range of 20 μg / ml to 100 μg / ml is within the scope of the present invention.

[0041] The drug containers of the Respimat® and Medspray® wet aerosol inhalers can be filled with 0.5 to 5 ml of the iloprost solution as described in the claims. Preferably, to avoid overdose, the filling amount is limited to the range of 0.5 to 2 ml or 0.5 to 1 ml. The drug container may contain 0.2 to 11 times (according to Ventavis® product information), preferably 1 to 5 times or 2 to 4 times, the maximum daily inhalation dose of iloprost of 45 μg. In one embodiment, the soft mist inhaler Respimat® or Medspray® is disposable; that is, the soft mist inhaler is discarded as a whole after delivering a predetermined number of sprays. In another embodiment, only the empty drug container is replaced, and the device is reused several times (e.g., 3 to 5 times) before replacement.

[0042] Patients treated with the compositions and methods disclosed herein suffer from pulmonary hypertension or other disorders of the pulmonary vascular system or pulmonary circulation. For example, a subject may belong to one of the following five groups of pulmonary hypertension according to the WHO.

[0043] Group 1 consists of pulmonary arterial hypertension (PAH), including subclasses 1.1 idiopathic PAH, 1.2 hereditary PAH, 1.3 drug and toxin-induced PAH, and 1.4 PAH associated with 1.4.1 connective tissue disease, 1.4.2 HIV infection, 1.4.3 portal hypertension, 1.4.4 congenital heart disease, and 1.4.5 schistosomiasis, 1.5 long-term PAH response to calcium channel blockers, 1.6 PAH with clear features of venous / capillary (PVOD / PCH) involvement, and 1.7 persistent PH in neonatal syndromes.

[0044] Group 2 consists of pulmonary hypertension due to left heart disease, including subclasses 2.1 PH due to heart failure with preserved LVEF, 2.2 PH due to heart failure with reduced LVEF, 2.3 valvular heart disease, and 2.4 congenital / acquired cardiovascular conditions leading to post-capillary PH.

[0045] Group 3: Pulmonary hypertension due to lung disease and / or hypoxia, including subclasses 3.1 obstructive pulmonary disease, 3.2 restrictive pulmonary disease, 3.3 other lung diseases with a restrictive / obstructive mixed pattern, 3.4 hypoxia without lung disease, and 3.5 developmental lung disease.

[0046] Group 4: Pulmonary hypertension due to pulmonary artery occlusion, including subclasses 4.1 chronic thromboembolic PH and 4.2 other pulmonary artery occlusion.

[0047] Group 5: Pulmonary hypertension with unknown and / or multifactorial mechanisms, including subclasses 5.1 hematological disorders, 5.2 systemic and metabolic disorders, 5.3 other, and 5.4 complex congenital heart disorders.

[0048] Preferably, the subject belongs to Group 1 or Group 4 PH in order to benefit from the methods and compositions provided for administering iloprost inhalable as PRN therapy. The subject may belong to Class I, Class II, Class III, or Class IV of the World Health Organization functional classification of pulmonary hypertension, as modified according to the functional classification of the New York Heart Association.

[0049] Patients may not be receiving drug therapy or may be receiving supportive therapy such as oral anticoagulants, diuretics, oxygen, or digoxin. In addition, treatment may include high-dose calcium channel blockers or approved pH-specific drugs, including endothelin receptor antagonists such as ambrisentan (oral), bosentan (oral), or macitentan (oral); phosphodiesterase type 5 inhibitors and guanylate cyclase stimulants or activators such as sildenafil (oral, intravenous), tadalafil (oral), vardenafil (oral), or riociguat (oral); and prostacyclin analogs and prostacyclin receptor agonists such as beraprost (oral), epoprostenol (intravenous), iloprost (aerosol, intravenous), treprostinil (aerosol, subcutaneous, intravenous, oral), or selexipag (oral). These drugs, primarily due to their vasodilatory effects, may be administered to patients as monotherapy or in combination therapy with two or more drugs simultaneously. Furthermore, the present invention also includes the use of future drugs specifically targeted at PH as a basic therapy, such drugs primarily focusing on typical characteristics of pulmonary vascular remodeling.

[0050] The PRN iloprost inhalation disclosed herein can be administered to patients who have not received prior treatment or who are receiving supportive care. Furthermore, PRN iloprost therapy may be administered in addition to chronic basic therapy using one or more medications specifically targeted at PH.

[0051] The pharmacodynamic profile of inhaled iloprost is well known. When administered over 10 minutes using a conventional nebulizer, the maximum therapeutic effect on hemodynamic parameters of the pulmonary circulation is observed approximately 5 minutes after the end of inhalation. Surprisingly, a significant vasodilatory effect in the pulmonary vascular system is already observed within 1 minute after rapid iloprost inhalation with 2-4 puffs per 1.25 μg of iloprost, maintaining the pulmonary selectivity of this approach. Based on the pharmacodynamic profile observed in Example 12, inhaled iloprost is a suitable ideal candidate for the treatment of PRN in pulmonary hypertension.

[0052] [Example 12] Iloprost PRN in patients with pulmonary hypertension A clinical pilot study was conducted in four patients to evaluate the feasibility of iloprost PRN. Eligible patients had a mean pulmonary artery pressure (PAP) higher than 25 mmHg and a pulmonary vascular resistance (PVR) of 240 dyn*s*cm. -5 The study included male and female patients aged 18–70 years with pulmonary arterial hypertension, characterized by a central venous pressure (CVP) higher than 3 mmHg and a pulmonary capillary wedge pressure (PCWP) lower than 12 mmHg. Patients were either treatment-naïve or receiving PH-specific drug therapy (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin analogs) alone or in combination. Patients were monitored by ECG, pulse oximetry, and non-invasive blood pressure measurement. Intracardiac catheterization was performed in the distal pulmonary artery to measure PAP, CVP, PCWP, and cardiac output. Heart rate, systemic arterial pressure (SAP), systemic vascular resistance (SVR), and central arterial and venous blood gases were also measured. After initial determination of all parameters, the responsiveness of the pulmonary vascular system to oxygen (2–4 L / min) and nitric oxide (20 ppm) was tested. Next, patients inhaled a single dose of 2.5 μg of iloprost sprayed into a prototype soft mist inhaler filled with iloprost at a concentration of 50 μg / ml in two breaths. Patient hemodynamic parameters and clinical status were assessed before inhalation and at 1, 5, 15, and 30 minutes post-inhalation. If no adverse effects were observed, a second inhalation procedure equivalent to a 5 μg dose of iloprost was performed in four breaths, followed by another observation period of at least 30 minutes. All patients were found to have good tolerability to the treatment. Pulmonary vascular therapeutic effects (shown by changes in PAP and PVR, see Figures 1 and 2) were already recorded within 1 minute of the completion of the inhalation procedure, and no serious systemic adverse events occurred (shown by changes in SAP and SVR, see Figures 3 and 4).

[0053] PRN iloprost is intended for the acute treatment of PH as needed, for example, to promote improved exercise tolerance and daily living activities, alleviate disease symptoms, or overcome acute pulmonary hypertension attacks. Using a portable soft mist inhaler such as Respimat® or Medspray®, patients can inhale an effective dose of PRN iloprost (up to 5 μg) up to 9 times a day, anytime, anywhere, resulting in a maximum daily dose of iloprost of 45 μg. In the method provided, if a patient is anticipating physical exercise or strenuous activity, or if a patient is experiencing shortness of breath, fatigue, dizziness, chest tightness or pain, edema, cyanosis, tachycardia, or palpitations, the subject should receive an inhalation of PRN iloprost preferably 0 to 15 minutes before starting such activity or during such activity or episode. Depending on individual needs, desired effects, and tolerability, patients may inhale a single puff, several puffs with short intervals between them, or several puffs with intervals of 15 seconds to 5 minutes between them. Patients who are not receiving daily prostanoids as a treatment specifically for PH typically inhale 0.4–2.5 μg of total iloprost per PRN treatment cycle, while patients chronically treated with prostanoids, particularly inhaled prostanoids, inhale 0.4–5 μg, preferably 2.5–5 μg, per PRN treatment cycle. The method provided herein provides PH patients with the potential to improve their quality of life by self-administering an effective dose of inhaled iloprost as needed, enabling them to cope with the requirements and challenges of daily living activities.

Claims

1. It is a soft mist inhaler, (a) A portable device filled with at least an effective amount of iloprost, (b) configured to dispense the effective amount of iloprost, (c) Configured to deliver the effective amount of iloprost in 1 to 10 ejections, (d) The soft mist inhaler is Respimat®, (e) The Respimat™ contains iloprost at a concentration of 20 μg / ml to 100 μg / ml and is further filled with an iloprost solution containing trometamol, 96% ethanol, sodium chloride, hydrochloric acid (for pH adjustment) and water for injection. (f) The effective amount of iloprost is 0.4 μg to 5 μg, (g) The amount of aerosol released is 10 μl to 25 μl, and 0.4 μg to 5 μg of iloprost is delivered in 1 to 10 ejaculations using the Respimat™. Soft mist inhaler.

2. A soft mist inhaler, (a) A portable device filled with at least an effective amount of iloprost, (b) configured to dispense the effective amount of iloprost, (c) The effective amount of iloprost is delivered by 1 to 5 ejections, (d) The soft mist inhaler is a Medspray® wet aerosol inhaler, (e) The Medspray® wet aerosol inhaler is filled with an iloprost solution containing iloprost at a concentration of 20 μg / ml to 100 μg / ml, and further containing trometamol, 96% ethanol, sodium chloride, hydrochloric acid (for pH adjustment), and sterile water for injection. (f) The effective amount of iloprost is 0.4 μg to 5 μg, (g) The amount of aerosol released is 20 μl to 50 μl, and 0.4 μg to 5 μg of iloprost is delivered in 1 to 5 puffs using the Medspray® wet aerosol inhaler. Soft mist inhaler.

3. The soft mist inhaler according to claim 1 or 2, wherein the effective amount of iloprost is delivered from the soft mist inhaler by 1 to 4 sprays.

4. The soft mist inhaler according to claim 1 or 2, wherein the volume of the drug container of the soft mist inhaler is 0.5 to 5 ml, and the drug container contains 0.2 to 11 times the approved maximum daily dose of iloprost, which is 45 μg.

5. The soft mist inhaler according to claim 1 or 2, wherein the volume of the drug container of the soft mist inhaler is 0.5 to 5 ml, and the drug container contains 2 to 5 times the approved maximum daily dose of iloprost, which is 45 μg.

6. The soft mist inhaler according to claim 1 or 2, wherein the volume of the drug container of the soft mist inhaler is 0.5 to 5 ml, and the drug container contains 2 to 4 times the approved maximum daily dose of iloprost, which is 45 μg.

7. The soft mist inhaler according to claim 1 or 2, wherein the volume of the drug container of the soft mist inhaler is 0.5 to 2 ml, and the drug container contains 0.2 to 11 times the approved maximum daily dose of iloprost, which is 45 μg.

8. The soft mist inhaler according to claim 1 or 2, wherein the volume of the drug container of the soft mist inhaler is 0.5 to 2 ml, and the drug container contains 2 to 5 times the approved maximum daily dose of iloprost, which is 45 μg.

9. The soft mist inhaler according to claim 1 or 2, wherein the volume of the drug container of the soft mist inhaler is 0.5 to 2 ml, and the drug container contains 2 to 4 times the approved maximum daily dose of iloprost, which is 45 μg.

10. The soft mist inhaler according to claim 1 or 2, wherein the volume of the drug container of the soft mist inhaler is 0.5 to 1 ml, and the drug container contains 0.2 to 11 times the approved maximum daily dose of iloprost, which is 45 μg.

11. The soft mist inhaler according to claim 1 or 2, wherein the volume of the drug container of the soft mist inhaler is 0.5 to 1 ml, and the drug container contains 2 to 5 times the approved maximum daily dose of iloprost, which is 45 μg.

12. The soft mist inhaler according to claim 1 or 2, wherein the volume of the drug container of the soft mist inhaler is 0.5 to 1 ml, and the drug container contains 2 to 4 times the approved maximum daily dose of iloprost, which is 45 μg.

13. The soft mist inhaler according to claim 1 or 2, wherein the aerosol generated from the soft mist inhaler has a volume median diameter (VMD) or aerodynamic median particle diameter (MMAD) in the range of 1 to 6 μm and a geometric standard deviation (GSD) in the range of 1.2 to 2.

14. The soft mist inhaler according to claim 1 or 2, wherein the aerosol generated from the soft mist inhaler has a volume median diameter (VMD) or aerodynamic median particle diameter (MMAD) in the range of 1 to 6 μm and a geometric standard deviation (GSD) in the range of 1.2 to 1.

8.

15. The soft mist inhaler according to claim 1 or 2, wherein the aerosol generated from the soft mist inhaler has a volume median diameter (VMD) or aerodynamic median particle diameter (MMAD) in the range of 2 to 5.5 μm and a geometric standard deviation (GSD) in the range of 1.2 to 2.

16. The soft mist inhaler according to claim 1 or 2, wherein the aerosol generated from the soft mist inhaler has a volume median diameter (VMD) or aerodynamic median particle diameter (MMAD) in the range of 2 to 5.5 μm and a geometric standard deviation (GSD) in the range of 1.2 to 1.

8.

17. The soft mist inhaler according to claim 1 or 2, wherein the soft mist inhaler is disposable.

18. The soft mist inhaler according to claim 1 or 2, wherein the empty drug container is replaceable and the soft mist inhaler can be reused multiple times.

19. The soft mist inhaler according to claim 1 or 2, wherein the empty drug container is replaceable and the soft mist inhaler can be reused 3 to 5 times.

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