Ensifentrine for the treatment of copd

Abstract

The present invention relates to a compound, which is encainide or a pharmaceutically acceptable salt thereof, for use in a method of treating COPD in a patient suffering from chronic obstructive pulmonary disease (COPD), wherein: the patient is resistant to improvement in lung function; and treating COPD comprises (i) improving the patient's COPD symptoms and / or (ii) improving the patient's quality of life. In some aspects, the compound is an inhalable pharmaceutical composition.

Description

[0001] Cross-references This application claims the benefit of U.S. Provisional Application No. 63 / 549608, the entirety of which is incorporated herein by reference. Technical Field

[0002] This invention relates to improving symptoms and / or quality of life in COPD patients using encefentin or a pharmaceutically acceptable salt thereof, said patients being those who exhibit a low FEV1 response after COPD treatment. Background Technology

[0003] Ensefentin ( N -(2-{(2 E )-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2 H -pyrimidino[6,1- a Isoquinoline-3(4) H RPL554 (also known as RPL554) is a dual PDE3 / PDE4 inhibitor and is described in WO 00 / 58308 A1.

[0004] As a combination PDE3 / PDE4 inhibitor, enstatin has bronchodilatory and anti-inflammatory activities and can be used to treat respiratory disorders, including chronic obstructive pulmonary disease (COPD). The chemical structure of enstatin is shown below.

[0005] .

[0006] There are many ways to treat COPD. Some methods attempt to improve lung function, such as by measuring an increase in forced expiratory volume in one second (FEV1). Other methods focus on the symptoms of COPD, such as by reducing symptoms or improving quality of life.

[0007] Different patients may respond differently to specific treatments for COPD, with some patients being more resistant to improvements in lung function. For example, some patients are more resistant to improvements in lung function following the administration of specific COPD treatments than others, with lower increases in FEV1 observed.

[0008] A lower response in lung function is often associated with less improvement in symptoms and / or quality of life. This means that patients who experience less improvement in lung function compared to other patients typically also experience less improvement in symptoms and quality of life, resulting in a poorer overall outcome of COPD treatment. Therefore, there is a desire to find COPD treatments that can improve symptoms and / or quality of life in COPD patients, even in those with limited responses in lung function. Summary of the Invention

[0009] A surprising finding of this invention is that enstatin can improve symptoms and / or quality of life in patients resistant to improvements in lung function, i.e., those who show relatively small improvements in lung function after COPD treatment. In patients who do not necessarily show significant improvements in lung function after treatment (e.g., as measured by changes in FEV1), enstatin can achieve meaningful positive effects on COPD symptoms and quality of life.

[0010] The present invention therefore provides a compound for use in a method of treating COPD in a patient with chronic obstructive pulmonary disease (COPD), said compound being enstatin or a pharmaceutically acceptable salt thereof, wherein: the patient is resistant to improvement of lung function; and treatment of COPD includes (i) improving the patient's COPD symptoms and / or (ii) improving the patient's quality of life. Typically, treatment of COPD includes improving the patient's COPD symptoms.

[0011] The present invention also provides a method for treating COPD in a patient with chronic obstructive pulmonary disease (COPD), wherein: the method comprises administering to the patient a therapeutically effective amount of a compound, said compound being encefentin or a pharmaceutically acceptable salt thereof; the patient is resistant to improvement of lung function; and the treatment of COPD comprises (i) improving the patient's COPD symptoms and / or (ii) improving the patient's quality of life.

[0012] The present invention further provides the use of a compound in the manufacture of a pharmaceutical agent for a method of treating COPD in a patient with chronic obstructive pulmonary disease (COPD), said compound being encefentin or a pharmaceutically acceptable salt thereof, wherein: the patient is resistant to improvement of lung function; and treatment of COPD includes (i) improving the patient's COPD symptoms and / or (ii) improving the patient's quality of life. Detailed Implementation

[0013] The patient is resistant to improvements in lung function. Therefore, this patient is less likely to experience improvements in lung function after treatments aimed at improving lung function, such as COPD treatment. This patient may experience, for example, below-average improvements in lung function after inhaled bronchodilators and / or anti-inflammatory agents. Lung function includes factors such as the amount of air the lungs can hold and the force required to expel air from the lungs. Lung function is typically assessed using spirometry, and key measures include forced expiratory volume in one second (FEV1), particularly the area under the curve (AUC) of FEV1 over 0–12 hours. 0–12 ) and the early morning valley value FEV1.

[0014] It has been found that enstatin or a pharmaceutically acceptable salt thereof can improve COPD symptoms and COPD quality of life (QoL), even in patients who show a limited response to improvement in lung function after reference COPD therapy (i.e., in patients resistant to improvement in lung function). As used herein, “reference COPD therapy” can be any treatment for COPD, such as any COPD therapy that can assess a patient’s lung function response to COPD therapy. Patients may or may not have experienced reference COPD therapy. For example, a patient may be one who is likely to show a low FEV1 response relative to baseline when they are given reference COPD therapy. As discussed further below, reference COPD therapy can be treatment with this compound (i.e., enstatin or a pharmaceutically acceptable salt thereof) or treatment with a different COPD therapy (e.g., a known bronchodilator).

[0015] Patients resistant to improvements in lung function are typically those who have shown a low FEV1 response relative to baseline after reference COPD treatment. Mentioning a low FEV1 response relative to baseline after reference COPD treatment includes patients who are prone to a low FEV1 response relative to baseline after reference COPD treatment, even if the patient has not yet received reference COPD treatment. Therefore, if the patient were given reference COPD treatment, the patient would exhibit a low FEV1 response. In some cases, the patient had previously received reference COPD treatment prior to treatment with this compound, and the patient had optionally been identified as exhibiting a low FEV1 response.

[0016] Low FEV1 response relative to baseline may include: less than 100 mL FEV1 AUC 0-12h An increase in FEV1; and / or an increase in morning trough FEV1 of less than 100 mL. For example, a low FEV1 response relative to baseline may include: less than approximately 60 mL of FEV1 AUC. 0-12h An increase in FEV1; and / or an increase in morning trough FEV1 of less than approximately 60 mL. In some cases, a low FEV1 response relative to baseline includes: less than 40 mL of FEV1 AUC. 0-12h An increase in FEV1; and / or an increase in morning trough FEV1 of less than 40 mL.

[0017] A low FEV1 response relative to baseline may include a specified FEV1 AUC. 0-12h The increase. A low FEV1 response relative to baseline may include a specified FEV1 AUC. 0-12h The increase of and the increase of the specified morning valley value FEV1.

[0018] Low FEV1 responses relative to baseline can include FEV1 AUCs of less than 60 mL, less than 40 mL, less than 20 mL, or less than 0 mL. 0-12h An increase in FEV1 relative to baseline can include increases in morning trough FEV1 of less than 60 mL, less than 40 mL, less than 20 mL, or less than 0 mL.

[0019] Following reference COPD treatment, patients can demonstrate FEV1 AUC of at least -300 mL, at least -100 mL, at least -50 mL, or at least 0 mL relative to baseline. 0-12h An increase in FEV1. Following reference COPD treatment, patients may show an increase in morning trough FEV1 of at least -300 mL, at least -100 mL, at least -50 mL, or at least 0 mL relative to baseline.

[0020] Following reference COPD treatment, patients may exhibit FEV1 AUC relative to baseline of -300 mL to 100 mL, -50 mL to 100 mL, -300 mL to 60 mL, -50 mL to 60 mL, 0 mL to 60 mL, -300 mL to 40 mL, -100 mL to 40 mL, 0 mL to 40 mL, or -20 mL to 20 mL. 0-12h The increase.

[0021] Following reference COPD treatment, patients may exhibit an increase in morning trough FEV1 relative to baseline: -300 mL to 100 mL, -50 mL to 100 mL, -300 mL to 60 mL, -50 mL to 60 mL, 0 mL to 60 mL, -300 mL to 40 mL, -100 mL to 40 mL, 0 mL to 40 mL, or -20 mL to 20 mL.

[0022] Typically, a low FEV1 response relative to baseline includes an increase of 100 mL to 60 mL, for example, 0 mL to 60 mL of morning trough FEV1.

[0023] Used as a reference for FEV1AUC 0-12h The baseline FEV1 change and the morning trough FEV1 change are typically measured by the average of two measurements taken on the day of the first dose of reference COPD treatment, before administration of reference COPD treatment, i.e., ≤ 40 minutes before administration and just before administration.

[0024] FEV1AUC 0-12hIt is defined as the area under the curve of FEV1 over 12 hours divided by 12 hours. FEV1 measurements are typically performed at 0.5, 1, 2, 4, 6, 8, and 12 hours after administration of reference COPD treatment.

[0025] Morning trough lung function can be measured by assessing a patient's FEV1 shortly before administering reference COPD treatment in the morning as part of maintenance therapy using reference COPD treatment. For example, FEV1 can be measured less than one hour before administering reference COPD treatment in the morning. Morning trough FEV1 can be FEV1 measured between 11.5 and 12 hours after the previous night's administration.

[0026] Low FEV1 response relative to baseline is typically measured after at least 6 weeks of treatment with reference COPD therapy. For example, low FEV1 response relative to baseline may be measured after at least 12 weeks of treatment with reference COPD therapy. Therefore, after at least 6 or 12 weeks of COPD therapy, a patient may be assessed as, or may be likely to, exhibit low FEV1 response as defined herein.

[0027] Typically, a low FEV1 response relative to baseline includes a FEV1 AUC of -200 mL to 40 mL. 0-12h An increase in FEV1, optionally after 12 weeks of maintenance therapy with reference COPD treatment. A low FEV1 response relative to baseline may include an increase in morning trough FEV1 of -100 mL to 30 mL, optionally after 12 weeks of maintenance therapy with reference COPD treatment.

[0028] Reference COPD treatment typically involves treatment with one or more bronchodilators. Reference COPD treatment may include 2 to 12 weeks of treatment with reference COPD medication. Reference COPD treatment may also include maintenance therapy with one or more bronchodilators.

[0029] The one or more bronchodilators used in reference COPD treatment are typically one or more of a β2-adrenergic agonist, a muscarinic receptor antagonist, and a phosphodiesterase 3 / 4 inhibitor. Muscarinic receptor antagonists are typically one or more of adecyl bromide, darotropium, tiotropium, glycopyrronium, and umeclidinium. β2-adrenergic agonists are typically one or more of salbutamol, salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abediterol, and carmocaterol. For example, after treatment with one or more bronchodilators (different from enstatin), patients may be prone to resistance to improvements in lung function, and this approach may include choosing to initiate treatment with a compound as enstatin or a pharmaceutically acceptable salt thereof.

[0030] Preferably, the one or more bronchodilators used in COPD treatment include encefentin or a pharmaceutically acceptable salt thereof. Therefore, patients may be resistant (or likely to be resistant) to improvements in lung function as defined above after treatment with encefentin or a pharmaceutically acceptable salt thereof. Therefore, the method may include improving COPD symptoms and / or the QoL of a COPD patient who exhibits a low FEV1 response relative to baseline after treatment with encefentin or a pharmaceutically acceptable salt thereof. For example, a method of treating COPD may include continuing treatment with the compound (encefentin or a pharmaceutically acceptable salt thereof) after determining that the patient has exhibited a low FEV1 response relative to baseline after treatment with the compound to improve the patient's COPD symptoms and / or the patient's quality of life.

[0031] Patients resistant to improvement in lung function can be defined as those who, after at least 6 weeks of daily administration of enstatin, show (or are likely to show) a FEV1 AUC of less than 100 mL relative to baseline. 0-12h Patients with an increase in FEV1 and / or an increase in morning trough FEV1 of less than 100 mL relative to baseline. For example, patients resistant to improvement in lung function are those who, after at least 12 weeks of daily administration of enstatin, show (or are likely to show) an FEV1 AUC of less than 40 mL relative to baseline. 0-12h Patients with an increase in FEV1 and / or an increase in morning trough FEV1 of less than 40 mL relative to baseline. In some cases, patients resistant to improvement in lung function are those who, after at least 12 weeks of daily administration of enstatin, have shown (or are likely to show) an increase in FEV1 AUC of -200 mL to 40 mL relative to baseline. 0-12h Patients with an increase in FEV1 and / or an increase in morning trough FEV1 relative to baseline -100 mL to 30 mL. As described in this article, daily administration of encefentin typically involves administering approximately 3 mg of encefentin twice daily.

[0032] The patient may have been identified as resistant to improvements in lung function. For example, a patient may have been observed to have a low FEV1 response relative to baseline after reference COPD treatment as defined herein. Therefore, the method may include the steps of identifying the patient as resistant to improvements in lung function and selecting the patient to be treated with the compound.

[0033] The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies COPD into four distinct stages: mild, moderate, severe, or very severe. The 2022 COPD report was published by Global Initiative for Chronic Obstructive Disease, Inc., and this document is incorporated herein by reference in its entirety.

[0034] The aforementioned stages of COPD can be classified as follows, where FEV1 is the forced expiratory volume in one second, and FVC is the forced vital capacity.

[0035] Mild COPD: FEV1 / FVC < 0.7 and FEV1 ≥ 80% of predicted value • Moderate COPD: FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80% of predicted value • Severe COPD: FEV1 / FVC < 0.7 and 30% ≤ FEV1 < 50% of predicted value • Extreme COPD: FEV1 / FVC < 0.7 and FEV1 < 30% of predicted value In each case, the patient's actual FEV1 is compared to a projected FEV1 value based on factors such as the patient's age and height. These projected values ​​are readily available to technicians, for example, from the National Health and Nutrition Examination Survey III (Hankinson JL, Odencrantz JR, Fedan KB. Spirometry reference values ​​from a sample of the general US Population. Am J RespirCrit Care. 1999; 159:179-187). An example of the equation used to calculate a patient's projected FEV1 (in L) is shown below, where H is height (cm) and A is age (years): ·Male: 0.0430H - 0.0290A - 2.490 ·Female: 0.0395H - 0.025A - 2.600 FEV1 and FVC, used to determine the severity of COPD in patients, are measured by spirometry shortly after administration of an adequate dose of at least one short-acting inhaled bronchodilator. Typically, FEV1 and FVC measurements for determining COPD severity are performed between 15 and 30 minutes after administration of salbutamol (Ventali).

[0036] Typically, as used herein, FEV1 and FVC are determined as described in the article Standardisation of spirometry, Eur J2005; 26; 319-338.

[0037] Therefore, a patient may have moderate COPD by measuring FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80% of the predicted FEV1 value, where FEV1 is the forced expiratory volume in one second and FVC is the forced vital capacity, measured between 15 and 30 minutes after a dose of bronchodilator. The severity of a patient's COPD can be determined at least one day before the first administration of the compound.

[0038] The patient may have a baseline FEV1 of at least 1500 mL, at least 2000 mL, or at least 2500 mL. For example, a patient may have a baseline FEV1 of 1500 mL to 5000 mL, or 2000 mL to 4000 mL. The patient typically has moderate, severe, or very severe COPD. For example, a patient may have moderate COPD. Alternatively, a patient may have severe or very severe COPD, such as severe COPD.

[0039] The patient may have irreversible COPD. Therefore, the patient may have irreversible airflow obstruction.

[0040] Patients with emphysema may be prone to developing resistance to the improvement in lung function after treatment. Therefore, the patient may have emphysema.

[0041] Treatment of COPD typically involves improving a patient's COPD symptoms. Improving COPD symptoms usually includes one or more of the following: reducing shortness of breath (dyspnea); reducing cough; reducing mucus production; reducing chest discomfort; and increasing physical activity. For example, improving COPD symptoms may include one or more of the following: reducing shortness of breath (dyspnea); reducing cough; and reducing mucus production. Improving COPD symptoms may also include reducing the frequency and / or severity of COPD exacerbations.

[0042] Treatment for COPD can include improving patients' COPD symptoms and improving their quality of life.

[0043] Treatment of COPD typically includes: (i) improving the patient's COPD symptoms, as measured by (a) a decrease of at least 2 on the Evaluating Respiratory Symptoms (E-RS) score or (b) an increase of at least 1 on the Transitional Dyspnea Index (TDI) score; and / or (ii) improving the patient's quality of life, as measured by a decrease of at least 4 on the St. George's Respiratory Questionnaire (SGRQ) score.

[0044] The E-RS score can be reduced by at least 3. The TDI score can be increased by at least 2. The SGRQ score can be reduced by at least 5 or at least 6.

[0045] Treatment of COPD may include reducing a patient's E-RS score by at least 2 and / or increasing a patient's TDI score by at least 1 relative to the patient's score within 24 hours prior to the first treatment with the compound. Treatment of COPD may include reducing the E-RS score as defined herein and increasing the TDI score as defined herein.

[0046] Changes in E-RS, TDI, and SGRQ scores typically occur at least 12 weeks after the patient's first treatment with the compound. Changes in E-RS, TDI, and SGRQ scores can occur at least 24 weeks after the patient's first treatment with the compound. For example, treatment of COPD with this compound may include reducing the patient's E-RS score by at least 2 and / or increasing the patient's TDI score by at least 1 after daily administration of the compound for at least 12 weeks.

[0047] The patient can be male. The patient can be female. The patient can be 65 years of age or older. The patient can be under 65 years of age. The patient may be receiving one or more background medications selected from long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA), and inhaled corticosteroids (ICS).

[0048] The compound is encefentin or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts are well known to those skilled in the art. Typically, the compound is encefentin (i.e., the free base of encefentin).

[0049] This method involves administering the compound to a patient, for example, by oral administration or by inhalation. The method typically involves administering the compound to a patient by inhalation. Pharmaceutical compositions comprising the compound and one or more pharmaceutically acceptable excipients or diluents are typically administered to a patient by inhalation, for example, via a nebulizer, a metered-dose inhaler (pMDI), or a dry powder inhaler (DPI).

[0050] Preferably, the method includes administering the compound to a patient by inhalation from a nebulizer. The nebulizer atomizes the liquid pharmaceutical composition into an aerosol for inhalation into the patient's respiratory tract. Examples of nebulizers include soft mist nebulizers, vibrating screen nebulizers, jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include Philips I-neb. TM (Philips), Philips SideStream (Philips), AeroNeb ® (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERxR TM Pulmonary Delivery System (AradigmCorp) and Pari LC Plus Reusable Nebuliser (Pari GmbH). Atomizers can be, for example, those with PARIVIOS. ® PRO Aerosol Delivery System PARI BOY ® The compressor is used in the Pari LC Sprint jet atomizer. The compound can be inhaled via the atomizer for 1 to 15 minutes.

[0051] Typically, the method involves administering the compound to a patient once, twice, or three times daily, for example, twice or three times daily. The compound can be administered to the patient by inhalation once, twice, or three times daily. Preferably, the method involves administering the compound to the patient twice daily by inhalation. The method may include administering a first dose of the compound in the morning (e.g., within 3 hours of waking up) and a second dose of the compound in the evening (e.g., within 3 hours of bedtime). Typically, the morning and evening doses are administered 10 to 14 hours apart, for example, approximately 12 hours apart.

[0052] This compound can be used at any suitable therapeutically effective amount. Typically, the daily dose of this compound is 0.1 to 20 mg. Generally, the method involves administering a total daily dose of 0.5 to 10 mg of this compound. Preferably, the total daily dose of this compound (e.g., encefentin free base) is 5 to 7 mg daily, for example, about 6 mg. As used herein, the term "about" can represent a variation of ±10% of the specified value. The total daily dose of this compound can be 6.0 mg.

[0053] Typically, the compound is administered twice daily in two separate doses, either the same or similar. For example, the method may include administering the compound to a patient twice daily in a first dose of 1 to 5 mg and a second dose of 1 to 5 mg. Alternatively, the method may include administering the compound to a patient twice daily in a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

[0054] Preferably, the method comprises administering two doses of approximately 3 mg of encefentin free base to a patient daily via inhalation. More preferably, the method comprises administering a dose of approximately 3 mg of the compound (3 mg BID) to a patient twice daily via inhalation. More preferably, the method comprises administering a dose of approximately 3 mg of the compound to a patient twice daily via a nebulizer. Each dose may be 3.0 mg of the free base encefentin administered via a nebulizer.

[0055] This compound is typically used as maintenance therapy. Generally, the method involves administering the compound to the patient at least once daily for at least 8 weeks. The compound may be administered to the patient at least once daily for at least 16 weeks, preferably at least 24 weeks. The compound may be administered to the patient daily for at least 1 year. The method may also include administering the compound to the patient at least once every 24 hours, preferably at least twice every 24 hours, for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

[0056] The compound is preferably administered as a suspension, i.e., a suspension containing particles of the compound in a diluent. Alternatively, the compound can be delivered as a dry powder, for example, a dry powder containing particles of the compound and particles of a carrier such as lactose.

[0057] This method typically involves administering an inhalable pharmaceutical composition comprising a suspension of particles containing the compound in a diluent. The particles containing the compound typically have a particle size distribution with a Dv50 of 0.5 µm to 5.0 µm. Preferably, the particles have a Dv50 of 1.0 µm to 2.0 µm.

[0058] This article refers to the Dv50 value to describe particle size, which is the median particle size of the volume distribution. Therefore, particles occupying half the volume have a diameter smaller than the Dv50 value, while particles occupying half the volume have a diameter larger than the Dv50 value. This is a well-known way of describing particle size distribution.

[0059] The technique used to measure Dv50 values, as described in this article, is typically laser diffraction. The particle size distribution of the particles containing the compound can be measured by laser diffraction using a wet powder dispersion system. For example, particle size distribution can be measured by laser diffraction using a Malvern Spraytec integrated with a wet dispersion cell. Typically, the instrument parameters for a Malvern Spraytec are as follows: • Particles - Standard opaque particles; • Particle refractive index - 1.50; • Refractive index (imaginary) - 0.50; • Particle density - 1.00; • The refractive index of the dispersant is -1.33; • Controller unit - 1000 RPM; • Measurement type - Timed; Initial sampling time - 30 seconds; • Shading - 20%-30%; • Dispersant - 1% Polysorbate 20 / Deionized Water

[0060] Particle size distribution can be measured using laser diffraction with the Malvern Mastersizer 3000. Typically, the instrument parameters for the Malvern Mastersizer 3000 are as follows: • Non-spherical particle mode: Yes • Refractive index: 1.500 • Absorption index: 0.500 • Particle density: 1.00 g / cm³ 3 • Dispersant name: 0.02% Polysorbate 20 / Water • Refractive index: 1.330 • Mixer; 1000 rpm • Sample measurement: 10 seconds • Shading: 10-20% The particles containing this compound typically contain encefentin (i.e., encefentin free base). The particles may contain at least 90% by weight of encefentin free base relative to the total weight of the particles. The particles may contain at least 99% by weight of encefentin. The particles may consist entirely of encefentin.

[0061] The concentration of particles containing the compound in an inhalable pharmaceutical composition is typically from 0.1 to 5.0 mg / mL, preferably from 0.1 to 2.5 mg / mL, and more preferably from 1.0 to 2.0 mg / mL.

[0062] In some embodiments, the concentration of encefenstein or a pharmaceutically acceptable salt thereof (e.g., encefenstein free base) in the inhalable pharmaceutical composition is at least 0.8 mg / mL. In some embodiments, the concentration of encefenstein or a pharmaceutically acceptable salt thereof (e.g., encefenstein free base) is at least about 0.9 mg / mL (e.g., 1 mg / mL, 1.1 mg / mL). In some embodiments, the concentration of encefenstein or a pharmaceutically acceptable salt thereof (e.g., encefenstein free base) is at most 1.5 mg / mL. The concentration of encefenstein or a pharmaceutically acceptable salt thereof (e.g., encefenstein free base) is at most 1.4 mg / mL (e.g., 1.3 mg / mL). In some embodiments, the concentration of encefenstein or a pharmaceutically acceptable salt thereof (e.g., encefenstein free base) is from about 1 mg / mL to about 1.4 mg / mL (e.g., 1.1 mg / mL to 1.3 mg / mL). In some embodiments, the concentration of encefentin or a pharmaceutically acceptable salt thereof (e.g., encefentin free base) is about 1.2 mg / mL. In some embodiments, the concentration of encefentin free base in the inhalable pharmaceutical composition is (e.g., about) 1.2 mg / mL.

[0063] Inhalable drug compositions typically further comprise one or more tension modifiers, one or more buffers, and one or more surfactants. Tension modifiers are typically sodium chloride.

[0064] In some embodiments, the tension modifier (e.g., sodium chloride) is present in the inhalable pharmaceutical composition at a concentration of at least 1 mg / mL (e.g., 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL). In some embodiments, the tension modifier (e.g., sodium chloride) is present in the inhalable pharmaceutical composition at a concentration of up to 15 mg / mL (e.g., 14 mg / mL, 13 mg / mL, 12 mg / mL, 11 mg / mL, 10 mg / mL, 9 mg / mL). In some embodiments, the tension modifier (e.g., sodium chloride) is present in the pharmaceutical composition at a concentration of about 1 mg / mL to about 15 mg / mL, about 3 mg / mL to about 10 mg / mL, about 4 mg / mL to about 10 mg / mL, about 5 mg / mL to about 11 mg / mL, about 5 mg / mL to about 9 mg / mL, or about 6 mg / mL to about 9 mg / mL. In some embodiments, the tension modifier (e.g., sodium chloride) is present in the inhalable pharmaceutical composition at a concentration of about 7 mg / mL to about 10 mg / mL. In some embodiments, the tension modifier (e.g., sodium chloride) is present in the inhalable pharmaceutical composition at a concentration of 8 mg / mL to 9 mg / mL. In some embodiments, the tension modifier (e.g., sodium chloride) is present in the inhalable pharmaceutical composition at a concentration of (e.g., about) 8.6 mg / mL.

[0065] Examples of buffers include citrate buffers, phosphate buffers, acetate buffers, and bicarbonate buffers. Preferably, the buffer is a phosphate buffer, such as sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate.

[0066] In some embodiments, the inhalable pharmaceutical compositions provided herein further comprise one or more buffers. In some embodiments, the one or more buffers comprise one or more of citrate buffers, phosphate buffers, acetate buffers, and / or bicarbonate buffers. In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer comprises sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate. In some embodiments, the buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the inhalable pharmaceutical composition at a concentration of at least 0.1 mg / mL (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.8 mg / mL, 1 mg / mL, or 1.4 mg / mL). In some embodiments, the buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the inhalable pharmaceutical composition at a concentration of 4 mg / mL (e.g., 3.8 mg / mL, 3.3 mg / mL, 2.8 mg / mL, 2.5 mg / mL, or 2 mg / mL). In some embodiments, a buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the inhalable pharmaceutical composition at a concentration of about 1 mg / mL to about 2 mg / mL, about 1.2 mg / mL to about 1.8 mg / mL, or about 1.4 mg / mL to about 1.7 mg / mL. In some embodiments, a buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the inhalable pharmaceutical composition at a concentration of about 1.5 mg / mL to about 1.7 mg / mL.

[0067] In some embodiments, the inhalable pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration of at least 0.1 mg / mL (e.g., 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL). In some embodiments, the inhalable pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration of up to 1.2 mg / mL (e.g., 1.1 mg / mL, 1.0 mg / mL, 0.9 mg / mL, 0.8 mg / mL). In some embodiments, the inhalable pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration of about 0.5 mg / mL to about 0.9 mg / mL. In some embodiments, the inhalable pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration of about 0.7 mg / mL to about 0.8 mg / mL. In some embodiments, the inhalable pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration of about 0.7 mg / mL. In some embodiments, the inhalable pharmaceutical composition comprises (e.g., approximately) 0.744 mg / mL of sodium dihydrogen phosphate dihydrate.

[0068] In some embodiments, the inhalable drug composition comprises a concentration of at least 0.1 mg / mL (e.g., 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL). In some embodiments, the inhalable drug composition comprises a concentration of up to 1.2 mg / mL (e.g., 1.1 mg / mL, 1.0 mg / mL, 0.9 mg / mL). In some embodiments, the inhalable drug composition comprises a concentration of about 0.7 mg / mL to about 1 mg / mL of disodium hydrogen phosphate dihydrate. In some embodiments, the inhalable drug composition comprises a concentration of about 0.8 mg / mL to about 0.9 mg / mL of disodium hydrogen phosphate dihydrate. In some embodiments, the inhalable drug composition comprises a concentration of about 0.8 mg / mL of disodium hydrogen phosphate dihydrate. In some embodiments, the inhalable drug composition comprises a concentration of about 0.9 mg / mL of disodium hydrogen phosphate dihydrate. In some embodiments, the inhalable pharmaceutical composition comprises (e.g., approximately) 0.853 mg / mL of disodium hydrogen phosphate dihydrate.

[0069] Examples of surfactants include lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76 and Brij 97), polypropylene glycol (e.g., PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glyceryl alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80), sorbitan alkyl esters (e.g., sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80) and sorbitan trioleate (Span 20)). 85), cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (poloxam), block copolymers of polyethylene glycol and polypropylene oxide (e.g., Pluronic surfactant), polyvinylpyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate, and polyethoxylated tallow amine (POEA).

[0070] Preferably, the one or more surfactants comprise polysorbate and / or alkyl sorbitan esters. The one or more surfactants may, for example, comprise polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). The one or more surfactants may, for example, comprise sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), or sorbitan trioleate (Span 85). Preferably, the sterile liquid medium comprises polysorbate 20 and / or sorbitan monolaurate (Span 20).

[0071] In some embodiments, the inhalable pharmaceutical composition comprises at least 0.01 mg / mL (e.g., 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL) of the one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate). In some embodiments, the inhalable pharmaceutical composition comprises at most 1 mg / mL (e.g., 0.9 mg / mL, 0.8 mg / mL, 0.7 mg / mL, 0.6 mg / mL) of the one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate). In some embodiments, the inhalable pharmaceutical composition comprises from about 0.3 mg / mL to about 0.7 mg / mL of the one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate). In some embodiments, the inhalable pharmaceutical composition comprises one or more of the surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.01 mg / mL to about 2 mg / mL. In some embodiments, the inhalable pharmaceutical composition comprises one or more of the surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the inhalable pharmaceutical composition comprises one or more of the surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.5 mg / mL. In some embodiments, the inhalable pharmaceutical composition comprises one or more of the surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.6 mg / mL. In some embodiments, the inhalable pharmaceutical composition comprises (e.g., about) 0.55 mg / mL of the surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate).

[0072] In some embodiments, the inhalable pharmaceutical composition comprises a concentration of polysorbate 20 (e.g., Tween 20) of at least 0.1 mg / mL (e.g., 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL). In some embodiments, the inhalable pharmaceutical composition comprises a concentration of polysorbate 20 (e.g., Tween 20) of up to 1 mg / mL (e.g., 0.9 mg / mL, 0.8 mg / mL, 0.7 mg / mL, 0.6 mg / mL). In some embodiments, the inhalable pharmaceutical composition comprises a concentration of polysorbate 20 (e.g., Tween 20) of from about 0.3 mg / mL to about 0.7 mg / mL. In some embodiments, the inhalable pharmaceutical composition comprises a concentration of polysorbate 20 (e.g., Tween 20) of from about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the inhalable pharmaceutical composition comprises a concentration of polysorbate 20 (e.g., Tween 20) of about 0.5 mg / mL.

[0073] In some embodiments, the inhalable pharmaceutical composition comprises a concentration of at least 0.01 mg / mL (e.g., 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL) of sorbitan monolaurate (Span 20). In some embodiments, the inhalable pharmaceutical composition comprises a concentration of up to 0.1 mg / mL (e.g., 0.09 mg / mL, 0.08 mg / mL, 0.07 mg / mL, 0.06 mg / mL) of sorbitan monolaurate (Span 20). In some embodiments, the inhalable pharmaceutical composition comprises a concentration of about 0.03 mg / mL to about 0.07 mg / mL of sorbitan monolaurate (Span 20). In some embodiments, the inhalable pharmaceutical composition comprises a concentration of about 0.04 mg / mL to about 0.06 mg / mL of sorbitan monolaurate (Span 20). In some embodiments, the inhalable pharmaceutical composition comprises (e.g., about) 0.05 mg / mL of sorbitan monolaurate (Span 20).

[0074] For example, the method may include administering an inhalable liquid drug composition to a patient, comprising: ·water; • Particles composed of encefentin free base at concentrations of 0.1 to 20 mg / mL; • One or more tension modifiers at a total concentration of 1.0 to 15 mg / mL; • One or more buffers with a total concentration of 0.1 to 4 mg / mL; and One or more surfactants with a total concentration of 0.05 to 3 mg / mL.

[0075] Inhalable liquid drug compositions may include: ·water; • Particles composed of encefentin free base at concentrations of 0.5 to 6 mg / mL; • Sodium chloride at a concentration of 5 to 12 mg / mL; • Sodium dihydrogen phosphate dihydrate at concentrations of 0.3 to 2 mg / mL; • Disodium hydrogen phosphate dihydrate at concentrations of 0.3 to 2 mg / mL; • Polysorbate 20 at concentrations of 0.1 to 1.5 mg / mL; and • Sorbitan monolaurate at concentrations of 0.01 to 0.5 mg / mL.

[0076] This compound can be used in combination with a second activator. The compound can be administered separately or simultaneously with the second activator. The patient may already be receiving the second activator as background therapy for COPD. Alternatively, treatment with the second activator can begin at approximately the same time as treatment with the compound. The compound and the second activator can be administered in a fixed combination.

[0077] The second active agent is typically selected from muscarinic receptor antagonists, β-adrenergic receptor agonists, and inhaled corticosteroids. Therefore, this compound can be used in combination with muscarinic receptor antagonists or β-adrenergic receptor agonists. The second active agent can be a long-acting muscarinic receptor antagonist (LAMA) or a long-acting β-adrenergic receptor agonist (LABA).

[0078] Examples of LAMAs include adetropium, darotropium, tiotropium, glycopyrronium, and umeclidinium. Examples of LABAs include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abediterol, and carmocaterol. Examples of inhaled corticosteroids include beclomethasone, budesonide, fluticasone propionate, cicsolone, mometasone, fluticasone furoate, and their pharmaceutically acceptable salts.

[0079] This compound can be used alternatively as a monotherapy. For example, it can be used as the sole active agent to treat COPD as defined herein. In some embodiments, the compound is not administered in combination with muscarinic receptor antagonists or beta-adrenergic receptor agonists.

[0080] The invention is described in more detail through the following embodiments. Example

[0081] Research Design A clinical study was conducted to determine the efficacy of encefentin in the treatment of COPD compared to placebo. Encefentin was administered via nebulizer at a dose of 3 mg twice daily (BID) for 24 weeks. The study was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial.

[0082] The study population included patients aged 40–80 years with moderate to severe COPD (FEV1 30%–70% pn, FEV1 / FVC ratio <0.7, mMRC ≥ 2). Randomization was stratified by (a) maintenance therapy with LAMA or LABA in a stable background (approximately 50%, yes or no) and (b) smoking (current or former). Inhaled corticosteroid (ICS) maintenance therapy was permitted in up to 20% of patients under certain provisions.

[0083] The primary endpoint was the mean area under the curve (AUC) of FEV1 at week 12 after administration. 0-12h Changes relative to baseline. COPD symptoms and quality of life (QoL) were also assessed in patients showing a lower response in lung function, particularly those with: (i) mean FEV1 AUC 0-12h (ii) Improvement of less than 100 mL, and (ii) improvement of less than 100 mL, less than 60 mL, or less than 40 mL in the morning trough FEV1.

[0084] method The severity of COPD is derived as follows: after bronchodilator administration at screening, mild: 80% <= FEV1, moderate: 50% <= FEV1 < 80% predicted, severe: 30% <= FEV1 < 50% predicted, and very severe: FEV1 < 30% predicted.

[0085] Baseline FEV1 is the average of two measurements taken on the first day before the study drug, i.e., ≤ 40 minutes before administration and just before administration, both on the first day before administration.

[0086] Average FEV1AUC 0-12h FEV1 is defined as the area under the curve of FEV1 over 12 hours divided by 12 hours. FEV1 measurements are typically performed at 0.5, 1, 2, 4, 6, 8, and 12 hours after administration. Morning trough FEV1 is defined as FEV1 assessed 11.5 to 12 hours after administration the previous night.

[0087] COPD exacerbation is defined as the worsening of two or more major symptoms (dyspnea, sputum volume, and purulent sputum) or any one major symptom worsening along with any one of the following minor symptoms: sore throat, cold, fever without other cause, and increased cough or wheezing for at least two consecutive days. COPD exacerbation is considered moderate severity if systemic corticosteroids and / or antibiotics are required, and severe if hospitalization is required.

[0088] COPD symptoms were assessed using the Ex-Respiratory Symptoms Assessment (E-RS; EXACT-Respiratory Symptoms, the minimum clinically significant difference (MCID) of the E-RS is -2 units of total score, User Manual (Version 3.0), October 2014) and the Temporal Dyspnea Index (TDI; Mahler et al., the MCID of the TDI is one unit of total score, COPD 2005, 2:99-103), and QoL was assessed using the St. George's Respiratory Questionnaire (SGRQ; Jones, St. George's Respiratory Questionnaire: MCID. COPD 2005, 2:75-79. The MCID of the SGRQ is -4 units of total score).

[0089] In the results: CI = confidence interval; CSR = clinical trial report; mITT = modified intention-to-treat.

[0090] preparation The study product and placebo are provided in ampoules as 2.5 mL units and administered via nebulizer. The formulations of the study product (encefentin suspension) and placebo are shown in Table 1. Element Concentration (mg / mL) Encerfentin particles (RPL554) 1.2 (for the active ingredient) or 0 (for the placebo) Polysorbate 20 (Tween 20) 0.50 Sorbitan monolaurate (Span 20) 0.05 Sodium dihydrogen phosphate dihydrate 0.744 Sodium hydrogen phosphate dihydrate 0.853 Sodium chloride 8.60 water qs to 1 mL Table 1.

[0091] result Meets the average FEV1 (AUC) of week 12. 0-12h The primary endpoint was [not specified]. All subgroups showed statistically significant improvements in lung function with the use of ensifine.

[0092] Average FEV 1 AUC 0-12h Patients with improvement less than 100 mL The mean FEV1 AUC at week 12 was less than 100 mL. 0-12hAnalysis of changes in symptoms and QoL relative to baseline confirmed a higher proportion of symptom and QoL responders among patients receiving entifine, and this effect was statistically and numerically greater than placebo at all weeks. Improvements in symptoms and QoL were observed in patients treated with entifine as early as week 6 at initial evaluation and persisted for 24 weeks.

[0093] Average FEV1AUC in Week 12 0-12h In this analysis of patients treated with enstatin and whose increase relative to baseline was less than 100 mL, at least two-thirds observed clinically significant symptom improvement after 24 weeks, and nearly half observed clinically significant QoL improvement. These improvements were significant in this subgroup, where approximately 60% of patients were receiving background LAMA or LABA therapy.

[0094] Table 2 shows the average FEV1 AUC with less than 100 mL. 0-12h Analysis of the proportion of patients with improved and clinically significant responses, including E-RS (-2 units), TDI (+1 unit), or SGRQ (-4 units) (combined with mITT).

[0095] In patients treated with enstatin vs. placebo, a nominally statistically significant 37% reduction in the rate and risk of moderate / severe exacerbations (measured by time to first event) was also observed in this patient group, consistent with the full mITT analysis.

[0096] a Multiple interpolation range method. Table 2.

[0097] Early morning valley FEV 1 Patients with improvement of less than 100 mL Analysis of symptom and QoL improvements in patients exhibiting a change of less than 100 mL in morning trough FEV1 relative to baseline confirmed a higher proportion of symptom and QoL responders in patients receiving ensifentin for 24 weeks, and this effect was numerically greater than placebo in all weeks. Improvements in symptoms and QoL were observed in patients treated with ensifentin as early as week 6 at initial evaluation and persisted for 24 weeks.

[0098] In this analysis of patients treated with enstatin whose morning trough FEV1 increase relative to baseline was less than 100 mL at week 12, at least two-thirds observed clinically significant symptom improvement after 24 weeks, and nearly half observed clinically significant QoL improvement. These improvements were significant in this subgroup, where approximately 60% of patients were receiving background LAMA or LABA therapy.

[0099] Table 3 shows an analysis of the proportion of patients with clinically significant responses, including a morning trough FEV1 of less than 100 mL and an E-RS (-2 units) or TDI (+1 unit) or SGRQ (-4 units) (combined with mITT).

[0100] A nominally statistically significant reduction of approximately 40% in the rate and risk of moderate / severe exacerbations (measured by time to first event) was also observed in patients treated with enstatin versus placebo, consistent with the full mITT analysis.

[0101] a Multiple interpolation range method Table 3.

[0102] Early morning valley FEV 1 Patients with improvement of less than 60 mL A similar analysis was performed in the group of patients whose morning trough FEV1 increase was less than 60 mL. This threshold was also assessed considering a large proportion of patients receiving background LAMA or LABA treatment. The results of this analysis are shown in Table 4 and demonstrate consistency with the analysis shown in Table 3, where the proportion of symptom or QoL responders was biased towards enstatin at all time points in both studies.

[0103] Table 4 shows an analysis of the proportion of patients with clinically significant responses, including a morning trough FEV1 of less than 60 mL and an E-RS (-2 units) or TDI (+1 unit) or SGRQ (-4 units) (combined with mITT).

[0104] a Multiple interpolation range method Table 4.

[0105] Early morning valley FEV 1 Patients with improvement of less than 40 mL A similar analysis was performed in the group of patients whose morning trough FEV1 increase was less than 40 mL. The results of this analysis are shown in Table 5 and demonstrate consistency with the analyses shown in Tables 3 and 4, in which the proportion of symptom or QoL responders was biased towards ensifine at all time points in both studies.

[0106] Table 5 shows an analysis of the proportion of patients with clinically significant responses, including a morning trough FEV1 of less than 40 mL and an E-RS (-2 units) or TDI (+1 unit) or SGRQ (-4 units) (combined with mITT).

[0107] Table 5.

[0108] in conclusion In summary, these analyses demonstrate that even in FEV1AUC 0-12h Significant positive effects on COPD symptoms, quality of life, and exacerbation were observed in a large proportion of patients treated with enstatin, with changes of <100 mL relative to baseline or changes of <100 mL, <60 mL, or <40 mL in morning trough FEV1 relative to baseline (achieving minimal clinically important differences (MCID) in symptoms and QoL in approximately 70% and 50% of subjects, respectively).

[0109] The effects observed in the encefentin treatment group were consistently higher than those observed in the placebo group. These analyses further confirm the efficacy of encefentin and support multiple pharmacological studies that cannot be characterized solely by its bronchodilatory effects.

[0110] Implementation Plan Other implementation plans include: 1. A compound for use in a method of treating COPD in a patient with chronic obstructive pulmonary disease (COPD), said compound being encefentin or a pharmaceutically acceptable salt thereof, wherein: The patient exhibited resistance to improvements in lung function; and Treatment of COPD includes (i) improving patients' COPD symptoms and / or (ii) improving patients' quality of life.

[0111] 2. The compound used according to embodiment 1, wherein the patient resistant to improvement in lung function is a patient who exhibits a low FEV1 response relative to baseline after reference COPD treatment. Optionally, the low FEV1 response relative to baseline includes: FEV1 AUC less than 100 mL 0-12h The increase; and / or Increase in morning trough FEV1 in amounts less than 100 mL.

[0112] 3. The compound used according to embodiment 2, wherein the low FEV1 response relative to baseline comprises an increase of less than about 60 mL in morning trough FEV1, optionally wherein the low FEV1 response relative to baseline comprises an increase of less than 40 mL in morning trough FEV1.

[0113] 4. The compound used according to embodiment 2 or embodiment 3, wherein the low FEV1 response relative to baseline comprises an increase of 100 mL to 60 mL in the morning trough FEV1.

[0114] 5. The compound used according to any one of embodiments 2 to 4, wherein the low FEV1 response relative to baseline is measured after at least 6 weeks of treatment with the reference COPD treatment, optionally after at least 12 weeks of treatment with the reference COPD treatment.

[0115] 6. The compound for use according to embodiment 5, wherein the reference COPD treatment comprises treatment with one or more bronchodilators, optionally wherein the reference COPD treatment comprises maintenance treatment with one or more bronchodilators.

[0116] 7. The compound used according to embodiment 6, wherein the one or more bronchodilators are one or more β2-adrenergic agonists, muscarinic receptor antagonists, and phosphodiesterase 3 / 4 inhibitors.

[0117] 8. The compound for use according to embodiment 6 or embodiment 7, wherein the one or more bronchodilators comprises encefentin or a pharmaceutically acceptable salt thereof.

[0118] 9. The compound used according to any of the foregoing embodiments, wherein the patient resistant to improvement of lung function is one who exhibits an FEV1AUC of less than 100 mL relative to baseline after daily administration of enstatin for at least 6 weeks. 0-12h Patients with increased FEV1 and / or an increase in morning trough FEV1 of less than 100 mL relative to baseline, Optionally, the patients who are resistant to the improvement in lung function are those who demonstrate a FEV1 AUC of less than 40 mL relative to baseline after daily administration of enstatin for at least 12 weeks. 0-12h Patients with increased FEV1 and / or an increase in morning trough FEV1 of less than 40 mL relative to baseline.

[0119] 10. The compound used according to any of the foregoing embodiments, wherein the patient has been identified as resistant to improvement of lung function, optionally wherein the patient has been observed to exhibit a low FEV1 response relative to baseline after reference COPD treatment as defined in any of embodiments 2 to 9.

[0120] 11. The compound used according to any of the foregoing embodiments, wherein the patient has a baseline FEV1 of at least 1500 mL, at least 2000 mL, or at least 2500 mL.

[0121] 12. The compound used according to any of the foregoing embodiments, wherein the patient suffers from moderate COPD, severe COPD or very severe COPD, preferably wherein the patient suffers from moderate COPD.

[0122] 13. The compound used according to any of the foregoing embodiments, wherein the patient suffers from irreversible COPD.

[0123] 14. The compound used according to any of the foregoing embodiments, wherein the patient suffers from emphysema.

[0124] 15. The compound used according to any of the foregoing embodiments, wherein treating COPD includes improving the patient's COPD symptoms.

[0125] 16. The compound used according to any of the foregoing embodiments, wherein improving COPD symptoms includes one or more of the following: reducing shortness of breath (dyspnea); reducing cough; reducing mucus production; reducing chest discomfort; and increasing physical activity.

[0126] 17. The compound used according to any of the foregoing embodiments, wherein treating COPD comprises: (i) Improvement of COPD symptoms in patients, as measured by a decrease of at least 2 on the patient's Exhalational Symptoms Assessment (E-RS) score or an increase of at least 1 on the patient's Period of Change Dyspnea Index (TDI) score; and / or (ii) Improve the patient’s quality of life, as measured by a reduction of at least 4 in the patient’s St. George’s Respiratory Questionnaire (SGRQ) score.

[0127] 18. The compound used according to any of the foregoing embodiments, wherein treating COPD comprises reducing the patient's E-RS score by at least 2 and / or increasing the patient's TDI score by at least 1 relative to the patient's score at the time of first treatment with the compound.

[0128] 19. The compound used according to embodiment 17 or embodiment 18, wherein the changes in E-RS, TDI and SGRQ scores are achieved at least 12 weeks after the patient is first treated with the compound, optionally at least 24 weeks after the patient is first treated with the compound.

[0129] 20. The compound for use according to any of the foregoing embodiments, wherein the method comprises administering the compound to a patient by inhalation, optionally wherein the method comprises administering the compound to a patient by inhalation via a nebulizer.

[0130] 21. The compound used according to any of the foregoing embodiments, wherein the compound is encefentin.

[0131] 22. The compound for use according to any of the foregoing embodiments, wherein the method comprises administering the compound to the patient once, twice, or three times daily.

[0132] 23. The compound for use according to any of the foregoing embodiments, wherein the method comprises administering the compound to the patient twice daily.

[0133] 24. The compound used according to any of the foregoing embodiments, wherein the method comprises administering the compound as a maintenance therapy.

[0134] 25. The compound used according to any of the foregoing embodiments, wherein the method comprises administering a total daily dose of 0.5 to 10 mg, preferably 5 to 7 mg, of the compound.

[0135] 26. The compound for use according to any of the foregoing embodiments, wherein the method comprises administering the compound to a patient twice daily at a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

[0136] 27. The compound used according to any of the foregoing embodiments, wherein the method comprises administering a dose of the compound (3 mg BID) to a patient twice daily, preferably wherein the method comprises administering a dose of the compound (3 mg BID) to a patient twice daily via a nebulizer.

[0137] 30. The compound used according to any of the foregoing embodiments, optionally wherein the method comprises administering the compound to a patient at least once daily for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

[0138] 31. The compound used according to any of the foregoing embodiments, wherein the compound is used in combination with a muscarinic receptor antagonist, a β-adrenergic receptor agonist, or an inhaled corticosteroid.

[0139] 32. A method of treating COPD in a patient with chronic obstructive pulmonary disease (COPD) who is resistant to improvement of lung function, comprising administering to the resistant patient a therapeutically effective amount of an inhalable pharmaceutical composition, the inhalable pharmaceutical composition comprising an amount of encefentin or a pharmaceutically acceptable salt thereof that effectively (i) improves COPD symptoms in the resistant patient and / or (ii) improves the quality of life of the resistant patient.

[0140] 33. The method of implementation scheme 32, wherein the patient resistant to improvement in lung function is a patient who exhibits a low FEV1 response relative to baseline after reference COPD treatment. Optionally, the low FEV1 response relative to baseline includes: FEV1 AUC less than 100 mL 0-12h The increase; and / or Increase in morning trough FEV1 in amounts less than 100 mL.

[0141] 34. The method of embodiment 33, wherein the low FEV1 response relative to baseline comprises an increase of less than about 60 mL of morning trough FEV1, optionally wherein the low FEV1 response relative to baseline comprises an increase of less than 40 mL of morning trough FEV1.

[0142] 35. The method of embodiment 33 or embodiment 34, wherein the low FEV1 response relative to baseline comprises an increase of 100 mL to 60 mL of morning trough FEV1.

[0143] 36. The method of any one of embodiments 33-35, wherein the low FEV1 response relative to baseline is measured after at least 6 weeks of treatment with the reference COPD treatment, optionally after at least 12 weeks of treatment with the reference COPD treatment.

[0144] 37. The method of embodiment 36, wherein the reference COPD treatment comprises treatment with one or more bronchodilators, optionally wherein the reference COPD treatment comprises maintenance treatment with one or more bronchodilators.

[0145] 38. The method of embodiment 37, wherein the one or more bronchodilators are one or more β2-adrenergic agonists, muscarinic receptor antagonists, and phosphodiesterase 3 / 4 inhibitors.

[0146] 39. The method of embodiment 37 or embodiment 38, wherein the one or more bronchodilators comprises encefentin or a pharmaceutically acceptable salt thereof.

[0147] 40. The method of any one of embodiments 32-39, wherein the patient resistant to improvement in lung function is defined as having an FEV1AUC of less than 100 mL relative to baseline after daily administration of enstatin for at least 6 weeks. 0-12h Patients with increased FEV1 and / or an increase in morning trough FEV1 of less than 100 mL relative to baseline, Optionally, the patients who are resistant to the improvement in lung function are those who demonstrate a FEV1 AUC of less than 40 mL relative to baseline after daily administration of enstatin for at least 12 weeks. 0-12h Patients with increased FEV1 and / or an increase in morning trough FEV1 of less than 40 mL relative to baseline.

[0148] 41. The method of any one of embodiments 32-40, wherein the patient has been identified as resistant to improvement in lung function, optionally wherein the patient has been observed to have a low FEV1 response relative to baseline after reference COPD treatment as defined in any one of embodiments 2 to 9.

[0149] 42. The method of any one of embodiments 32-41, wherein the patient has a baseline FEV1 of at least 1500 mL, at least 2000 mL, or at least 2500 mL.

[0150] 43. The method according to any one of embodiments 32-42, wherein the patient has moderate COPD, severe COPD or very severe COPD, preferably wherein the patient has moderate COPD.

[0151] 44. The method of any one of implementation schemes 32-43, wherein the patient suffers from irreversible COPD.

[0152] 45. The method of any one of embodiments 32-44, wherein the patient suffers from emphysema.

[0153] 46. ​​The method of any one of implementations 32-45, wherein treating COPD includes improving the patient's COPD symptoms.

[0154] 47. The method of any one of 32-46, wherein improving COPD symptoms includes one or more of the following: reducing shortness of breath (dyspnea); reducing cough; reducing mucus production; reducing chest discomfort; and increasing physical activity.

[0155] 48. The method of any one of implementations 32-47, wherein the treatment of COPD includes: (i) Improvement of COPD symptoms in patients, as measured by a decrease of at least 2 on the patient's Exhalational Symptoms Assessment (E-RS) score or an increase of at least 1 on the patient's Period of Change Dyspnea Index (TDI) score; and / or (ii) Improve the patient’s quality of life, as measured by a reduction of at least 4 in the patient’s St. George’s Respiratory Questionnaire (SGRQ) score.

[0156] 49. The method of any one of embodiments 32-48, wherein treating COPD includes reducing the patient's E-RS score by at least 2 and / or increasing the patient's TDI score by at least 1 relative to the patient's score at the time of first treatment with the inhalable drug composition.

[0157] 50. The method of embodiment 48 or embodiment 49, wherein the changes in E-RS, TDI and SGRQ scores are achieved at least 12 weeks after the patient is first treated with the inhalable pharmaceutical composition, optionally at least 24 weeks after the patient is first treated with the inhalable pharmaceutical composition.

[0158] 51. The method of any one of embodiments 32-50, wherein the method comprises administering the inhalable drug composition to a patient by inhalation, optionally wherein the method comprises administering the inhalable drug composition to a patient by inhalation via a nebulizer.

[0159] 52. The method of any one of embodiments 32-51, wherein the compound is encefentin.

[0160] 53. The method according to any one of embodiments 32-52, wherein the method comprises administering the inhalable drug composition to a patient once, twice or three times daily.

[0161] 54. The method of any one of embodiments 32-53, wherein the method comprises administering the inhalable pharmaceutical composition to a patient twice daily.

[0162] 55. The method of any one of embodiments 32-54, wherein the method comprises administering the inhalable pharmaceutical composition as a maintenance therapy.

[0163] 56. The method of any one of embodiments 32-55, wherein the method comprises administering a total daily dose of 0.5 to 10 mg, preferably 5 to 7 mg, of the compound.

[0164] 57. The method of any one of embodiments 32-56, wherein the method comprises administering the compound to a patient twice daily at a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

[0165] 58. The method of any one of embodiments 32-57, wherein the method comprises administering a dose of the compound (3 mg BID) to a patient twice daily, preferably wherein the method comprises administering a dose of the compound (3 mg BID) to a patient twice daily via a nebulizer.

[0166] 59. The method of any one of embodiments 32-58, wherein the method optionally includes administering the inhalable drug composition to a patient at least once daily for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

[0167] 60. The method of any one of embodiments 32-59, wherein the inhalable pharmaceutical composition is used in combination with a muscarinic receptor antagonist, a β-adrenergic receptor agonist, or an inhaled corticosteroid.

[0168] 61. The method of any one of embodiments 32-60, wherein the inhalable pharmaceutical composition comprises a suspension of encefentin particles containing encefentin or a pharmaceutically acceptable salt thereof in a diluent.

[0169] 62. The method of any one of embodiments 32-61, wherein the inhalable drug composition comprises: a. Encerfinite particle; b. Buffer; c. One or more surfactants; and d. Tension regulator, The total weight of encefentin or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical composition is approximately 2.7 mg to approximately 3.3 mg.

[0170] 63. The method of any one of embodiments 32-61, wherein the inhalable pharmaceutical composition comprises: a. Encerfentin particles at concentrations of approximately 1 mg / mL to approximately 1.4 mg / mL; b. Buffers at concentrations of approximately 1 mg / mL to approximately 2 mg / mL; c. One or more surfactants at a total concentration of about 0.01 mg / mL to about 0.8 mg / mL; and d. Tension modulators at concentrations of approximately 5 mg / mL to approximately 10 mg / mL.

[0171] 64. The method of any one of embodiments 32-61, wherein the inhalable pharmaceutical composition comprises: a. Encerfentin particles at concentrations of approximately 1 mg / mL to approximately 1.4 mg / mL; b. Polysorbate 20 (Tween 20) at concentrations of approximately 0.3 mg / mL to approximately 0.7 mg / mL; c. Sorbitan monolaurate (Span 20) at concentrations from 0 mg / mL to approximately 0.1 mg / mL. d. Sodium dihydrogen phosphate dihydrate at concentrations of approximately 0.5 mg / mL to approximately 1 mg / mL; e. Sodium hydrogen phosphate dihydrate at concentrations of approximately 0.5 mg / mL to approximately 1 mg / mL; and f. Sodium chloride at a concentration of approximately 5 mg / mL to approximately 10 mg / mL.

[0172] 65. The method of any one of embodiments 32-61, wherein the inhalable pharmaceutical composition comprises: a. Encerfentin particles at a concentration of 1.2 mg / mL; b. Polysorbate 20 (Tween 20) at a concentration of 0.5 mg / mL; c. Sorbitan monolaurate at a concentration of 0.05 mg / mL (Span 20); Sodium dihydrogen phosphate dihydrate at a concentration of 0.744 mg / mL; e. 0.853 mg / mL of disodium hydrogen phosphate dihydrate; and f. 8.6 mg / mL of sodium chloride.

[0173] 66. The method of any one of embodiments 32-61, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.4 mg / mL Encerfentin particles; b. 0.55 mg / ml polysorbate 20; c. 0.744 mg / ml sodium dihydrogen phosphate dihydrate; d. 0.853 mg / ml disodium hydrogen phosphate dihydrate; e. 8.6 mg / ml sodium chloride; and f. Water.

[0174] 67. The method of any one of embodiments 32-61, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.3 mg / mL Encerfentin particles; b. 0.55 mg / ml sorbitan monolaurate; c. 0.744 mg / ml sodium dihydrogen phosphate dihydrate; d. 0.853 mg / ml disodium hydrogen phosphate dihydrate; e. 8.6 mg / ml sodium chloride; and f. Water.

[0175] 68. The method of any one of embodiments 32-61, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.3 mg / mL Encerfentin particles; b. 0.5 mg / ml polysorbate 20; c. 0.05 mg / ml sorbitan monolaurate; d. 1.1 mg / ml sodium dihydrogen phosphate dihydrate; e. 0.9 mg / ml disodium hydrogen phosphate dihydrate; f. 13 mg / ml sodium chloride; and g. Water.

[0176] 69. The method of any one of embodiments 32-61, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.2 mg / mL Encerfentin particles; b. 0.4 mg / ml polysorbate 20; c. 0.10 mg / ml sorbitan monolaurate; d. 0.744 mg / ml sodium dihydrogen phosphate dihydrate; e. 0.853 mg / ml disodium hydrogen phosphate dihydrate; f. 8.6 mg / ml sodium chloride; and g. Water.

[0177] 70. The method of any one of embodiments 32-61, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.4 mg / mL Encerfentin particles; b. 0.4 mg / ml polysorbate 20; c. 0.04 mg / ml sorbitan monolaurate; d. 1.2 mg / ml sodium dihydrogen phosphate dihydrate; e. 8.6 mg / ml sodium chloride; and f. Water.

[0178] 71. The method of any one of embodiments 32-61, wherein the inhalable drug composition comprises: a. Encerfentin particles at concentrations of 0.8 to 1.4 mg / mL; b. One or more surfactants at a total concentration of 0.3 to 0.7 mg / mL; c. One or more buffers with a total concentration of 1.0 to 2.0 mg / ml; d. One or more tension modifiers at concentrations from 1.0 to 15.0 mg / ml and e. Water.

[0179] While particularly preferred embodiments have been described above, it is to be understood that this disclosure is not limited thereto. Those skilled in the art will appreciate that various modifications can be made to the disclosed embodiments, and such modifications are intended to fall within the scope of this invention.

[0180] All publications, patent applications and patents cited in this specification are incorporated herein by reference in their entirety.

Claims

1. A compound for use in a method of treating COPD in a patient with chronic obstructive pulmonary disease (COPD), said compound being encefentin or a pharmaceutically acceptable salt thereof, wherein: The patient exhibited resistance to improvements in lung function; and Treatment of COPD includes (i) improving patients' COPD symptoms and / or (ii) improving patients' quality of life.

2. The compound for use according to claim 1, wherein the patient resistant to improvement in lung function is a patient who exhibits a low FEV1 response relative to baseline after reference COPD treatment. Optionally, the low FEV1 response relative to baseline includes: FEV1 AUC less than 100 mL 0-12h The increase; and / or Increase in morning trough FEV1 in amounts less than 100 mL.

3. The compound for use according to claim 2, wherein the low FEV1 response relative to baseline comprises an increase of less than about 60 mL in morning trough FEV1, optionally wherein the low FEV1 response relative to baseline comprises an increase of less than 40 mL in morning trough FEV1.

4. The compound for use according to claim 2 or claim 3, wherein the low FEV1 response relative to baseline comprises an increase of 100 mL to 60 mL in the morning trough FEV1.

5. The compound for use according to any one of claims 2 to 4, wherein the low FEV1 response relative to baseline is measured after at least 6 weeks of treatment with the reference COPD treatment, optionally after at least 12 weeks of treatment with the reference COPD treatment.

6. The compound for use according to claim 5, wherein the reference COPD treatment comprises treatment with one or more bronchodilators, optionally wherein the reference COPD treatment comprises maintenance treatment with one or more bronchodilators.

7. The compound for use according to claim 6, wherein the one or more bronchodilators are one or more β2-adrenergic agonists, muscarinic receptor antagonists, and phosphodiesterase 3 / 4 inhibitors.

8. The compound for use according to claim 6 or claim 7, wherein the one or more bronchodilators comprises encefentin or a pharmaceutically acceptable salt thereof.

9. The compound for use according to any one of the preceding claims, wherein the patient resistant to improvement in lung function is one who exhibits an FEV1AUC of less than 100 mL relative to baseline after daily administration of enstatin for at least 6 weeks. 0-12h Patients with increased FEV1 and / or an increase in morning trough FEV1 of less than 100 mL relative to baseline, Optionally, the patients who are resistant to the improvement in lung function are those who demonstrate a FEV1 AUC of less than 40 mL relative to baseline after daily administration of enstatin for at least 12 weeks. 0-12h Patients with increased FEV1 and / or an increase in morning trough FEV1 of less than 40 mL relative to baseline.

10. The compound for use according to any one of the preceding claims, wherein the patient has been identified as resistant to improvement in lung function, optionally wherein the patient has been observed to exhibit a low FEV1 response relative to baseline after reference COPD treatment as defined in any one of claims 2 to 9.

11. The compound for use according to any one of the preceding claims, wherein the patient has a baseline FEV1 of at least 1500 mL, at least 2000 mL, or at least 2500 mL.

12. The compound for use according to any one of the preceding claims, wherein the patient suffers from moderate, severe, or very severe COPD, preferably wherein the patient suffers from moderate COPD.

13. The compound for use according to any one of the preceding claims, wherein the patient suffers from irreversible COPD.

14. The compound for use according to any one of the preceding claims, wherein the patient suffers from emphysema.

15. The compound for use according to any one of the preceding claims, wherein treating COPD includes improving COPD symptoms in a patient.

16. The compound for use according to any one of the preceding claims, wherein improving COPD symptoms includes one or more of the following: reducing shortness of breath (dyspnea); reducing cough; reducing mucus production; reducing chest discomfort; and increasing physical activity.

17. The compound for use according to any one of the preceding claims, wherein treating COPD comprises: (i) Improvement of COPD symptoms in patients, as measured by a decrease of at least 2 on the patient's Exhalational Symptoms Assessment (E-RS) score or an increase of at least 1 on the patient's Period of Change Dyspnea Index (TDI) score; and / or (ii) Improve the patient’s quality of life, as measured by a reduction of at least 4 in the patient’s St. George’s Respiratory Questionnaire (SGRQ) score.

18. The compound for use according to any one of the preceding claims, wherein treating COPD comprises reducing the patient's E-RS score by at least 2 and / or increasing the patient's TDI score by at least 1 relative to the patient's score at the time of first treatment with the compound.

19. The compound for use according to claim 17 or claim 18, wherein the changes in E-RS, TDI, and SGRQ scores are achieved at least 12 weeks after the patient is first treated with the compound, optionally at least 24 weeks after the patient is first treated with the compound.

20. The compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to a patient by inhalation, optionally wherein the method comprises administering the compound to a patient by inhalation via a nebulizer.

21. The compound for use according to any one of the preceding claims, wherein the compound is encefentin.

22. The compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to a patient once, twice, or three times daily.

23. The compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to a patient twice daily.

24. The compound for use according to any one of the preceding claims, wherein the method comprises administering the compound as a maintenance therapy.

25. The compound for use according to any one of the preceding claims, wherein the method comprises administering a total daily dose of 0.5 to 10 mg, preferably 5 to 7 mg, of the compound.

26. The compound for use according to any one of the preceding claims, wherein the method comprises administering the compound to a patient twice daily at a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

27. The compound for use according to any one of the preceding claims, wherein the method comprises administering a dose of the compound (3 mg BID) to a patient twice daily, preferably wherein the method comprises administering a dose of the compound (3 mg BID) to a patient twice daily via a nebulizer.

28. The compound for use according to any one of the preceding claims, optionally wherein the method comprises administering the compound to a patient at least once daily for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

29. The compound for use according to any one of the preceding claims, wherein the compound is used in combination with a muscarinic receptor antagonist, a β-adrenergic receptor agonist, or an inhaled corticosteroid.

30. A method for treating COPD in a patient with chronic obstructive pulmonary disease (COPD), wherein: The method includes administering a therapeutically effective amount of a compound to the patient, the compound being encefentin or a pharmaceutically acceptable salt thereof; The patient exhibited resistance to improvements in lung function; and Treatment of COPD includes (i) improving patients' COPD symptoms and / or (ii) improving patients' quality of life.

31. The compound of claim 1, wherein the compound is administered to a patient in an inhalable pharmaceutical composition comprising a suspension of encefentin particles containing encefentin or a pharmaceutically acceptable salt thereof in a diluent.

32. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition comprises: a. Encerfinite particle; b. Buffer; c. One or more surfactants; and d. Tension regulator, The total weight of encefentin or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical composition is approximately 2.7 mg to approximately 3.3 mg.

33. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition comprises: a. Encerfentin particles at concentrations of approximately 1 mg / mL to approximately 1.4 mg / mL; b. Buffers at concentrations of approximately 1 mg / mL to approximately 2 mg / mL; c. One or more surfactants at a total concentration of about 0.01 mg / mL to about 0.8 mg / mL; and d. Tension modulators at concentrations of approximately 5 mg / mL to approximately 10 mg / mL.

34. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition comprises: a. Encerfentin particles at concentrations of approximately 1 mg / mL to approximately 1.4 mg / mL; b. Polysorbate 20 (Tween 20) at concentrations of approximately 0.3 mg / mL to approximately 0.7 mg / mL; c. Sorbitan monolaurate (Span 20) at concentrations from 0 mg / mL to approximately 0.1 mg / mL. d. Sodium dihydrogen phosphate dihydrate at concentrations of approximately 0.5 mg / mL to approximately 1 mg / mL; e. Sodium hydrogen phosphate dihydrate at concentrations of approximately 0.5 mg / mL to approximately 1 mg / mL; and f. Sodium chloride at a concentration of approximately 5 mg / mL to approximately 10 mg / mL.

35. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition comprises: a. Encerfentin particles at a concentration of 1.2 mg / mL; b. Polysorbate 20 (Tween 20) at a concentration of 0.5 mg / mL; c. Sorbitan monolaurate at a concentration of 0.05 mg / mL (Span 20); Sodium dihydrogen phosphate dihydrate at a concentration of 0.744 mg / mL; e. 0.853 mg / mL of disodium hydrogen phosphate dihydrate; and f. 8.6 mg / mL of sodium chloride.

36. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.4 mg / mL Encerfentin particles; b. 0.55 mg / ml polysorbate 20; c. 0.744 mg / ml sodium dihydrogen phosphate dihydrate; d. 0.853 mg / ml disodium hydrogen phosphate dihydrate; e. 8.6 mg / ml sodium chloride; and f. Water.

37. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.3 mg / mL Encerfentin particles; b. 0.55 mg / ml sorbitan monolaurate; c. 0.744 mg / ml sodium dihydrogen phosphate dihydrate; d. 0.853 mg / ml disodium hydrogen phosphate dihydrate; e. 8.6 mg / ml sodium chloride; and f. Water.

38. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.3 mg / mL Encerfentin particles; b. 0.5 mg / ml polysorbate 20; c. 0.05 mg / ml sorbitan monolaurate; d. 1.1 mg / ml sodium dihydrogen phosphate dihydrate; e. 0.9 mg / ml disodium hydrogen phosphate dihydrate; f. 13 mg / ml sodium chloride; and g. Water.

39. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.2 mg / mL Encerfentin particles; b. 0.4 mg / ml polysorbate 20; c. 0.10 mg / ml sorbitan monolaurate; d. 0.744 mg / ml sodium dihydrogen phosphate dihydrate; e. 0.853 mg / ml disodium hydrogen phosphate dihydrate; f. 8.6 mg / ml sodium chloride; and g. Water.

40. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition is a suspension comprising: a. 1.4 mg / mL Encerfentin particles; b. 0.4 mg / ml polysorbate 20; c. 0.04 mg / ml sorbitan monolaurate; d. 1.2 mg / ml sodium dihydrogen phosphate dihydrate; e. 8.6 mg / ml sodium chloride; and f. Water.

41. The compound for use according to claim 31, wherein the inhalable pharmaceutical composition comprises: a. Encerfentin particles at concentrations of 0.8 to 1.4 mg / mL; b. One or more surfactants at a total concentration of 0.3 to 0.7 mg / mL; c. One or more buffers with a total concentration of 1.0 to 2.0 mg / ml; d. One or more tension modifiers at concentrations from 1.0 to 15.0 mg / ml and e. Water.

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