Pharmaceutical compositions of enciferstat for chronic obstructive pulmonary disease

Abstract

Provided herein are pharmaceutical compositions and methods for providing plasma concentrations of encainide for a particular patient population, including those with impaired renal or hepatic alterations. In some aspects, the compound is in an inhalable pharmaceutical composition.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 550792, filed February 7, 2024, which is incorporated herein by reference in its entirety. Background Technology

[0002] Encefentin (N-(2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl}ethyl)urea; also known as RPL554) is a dual PDE3 / PDE4 inhibitor and is described in WO 00 / 58308 A1.

[0003] As a combination PDE3 / PDE4 inhibitor, enstatin possesses both bronchodilatory and anti-inflammatory activities and can be used to treat respiratory conditions including chronic obstructive pulmonary disease (COPD). The chemical structure of enstatin is shown below.

[0004] COPD is a progressive, long-term condition that can be experienced by patients at varying levels of severity. Symptoms of COPD (e.g., shortness of breath and cough) can range from mild to severe, and different treatment options may be preferred for different degrees of COPD severity. Treatment for COPD typically includes maintenance therapy, in which subjects receive medication regularly (e.g., once or twice daily) to improve lung function and alleviate COPD symptoms. Summary of the Invention

[0005] This article provides pharmaceutical compositions and methods for treating COPD. In some cases, the methods provided herein include treating specific subgroups of COPD subjects, including subjects with varying renal or hepatic function who may experience altered enstatin exposure and clearance. It is estimated that approximately 15% of U.S. adults have chronic kidney disease (e.g., approximately 37 million people). More than 100 million people in the United States have some form of liver disease (e.g., hepatic impairment). Given the large population of individuals with altered renal or hepatic function, it is desirable to provide subjects experiencing altered renal or hepatic function (e.g., a decline in either function) with an enstatin plasma concentration having the desired pharmacokinetic profile. This article provides methods for providing enstatin plasma concentrations with the desired pharmacokinetic profile for subjects with normal to mild renal impairment, and for subjects with moderate renal impairment. This article also provides methods for providing enstatin plasma concentrations with the desired pharmacokinetic profile for subjects with healthy hepatic function, moderate hepatic impairment, or severe hepatic impairment. The development of methods for treating subjects with altered renal or hepatic conditions is desirable for obtaining dosage forms suitable for said patient populations.

[0006] In some embodiments, this document provides a method for treating chronic obstructive pulmonary disease (COPD) in human subjects with moderate renal impairment, the method comprising administering a liquid pharmaceutical composition to the human subject containing a therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the human subject has an absolute estimated glomerular filtration rate (aEGFR) of less than 60 mL / min. In some embodiments, the liquid pharmaceutical composition provides a plasma concentration of encefentin after administration to the human subject by inhalation, the plasma concentration containing an average Cg of about 500 pg / mL to about 700 pg / mL. max In some embodiments, the plasma concentration comprises an average Cg of about 550 pg / mL to about 650 pg / mL. max In some implementations, the plasma concentration comprises an average Cg of approximately 604 pg / mL. max In some implementations, C max Compared to subjects who received the liquid drug composition via inhalation and did not have moderate renal impairment, C max At least 10% higher. In some embodiments, the plasma concentration comprises an average AUC of approximately 2600 pg / mL*h to approximately 3600 pg / mL*h. 0-tau In some embodiments, the plasma concentration comprises an average AUC of approximately 3000 pg / mL*h to approximately 3400 pg / mL*h. 0-tau In some implementations, the plasma concentration comprises an average AUC of approximately 3200 pg / mL*h. 0-tauIn some implementations, the average AUC 0-tau Compared with the mean AUC of subjects who received the liquid drug composition by inhalation and did not have moderate renal impairment. 0-tau At least 25% higher. In some implementations, the plasma concentration includes an average T value over approximately 1 to 2 hours. max In some implementations, the plasma concentration comprises an average Tg of approximately 1.2 hours to approximately 1.7 hours. max In some implementations, the average C max Average AUC 0-tau and average T max Measurements were taken at intervals, which included two or more of the following: 1.0 hour (±0.5 hours), 1.5 hours (±0.5 hours), 2.5 hours (±0.5 hours), 3.0 hours (±0.5 hours), 4.0 hours (±1 hour), 6.0 hours (±1 hour), 8.0 hours (±1 hour), 10.0 hours (±1 hour), 12.0 hours (±1 hour), 24.0 hours (±1 hour), 36.0 hours (±1 hour), 48.0 hours (±1 hour), 56.0 hours (±1 hour), and 60.0 hours (±1 hour) after administration of the liquid pharmaceutical composition.

[0007] In some embodiments, this document provides a method for treating chronic obstructive pulmonary disease (COPD) in human subjects having liver function ranging from healthy to moderately impaired or severely impaired. The method comprises administering to the human subject a liquid pharmaceutical composition comprising a therapeutically effective amount of enstatin or a pharmaceutically acceptable salt thereof, wherein the liquid pharmaceutical composition provides a plasma concentration of enstatin containing AUCt,ss that is substantially the same for subjects with healthy liver function, moderate to severe impaired liver function, or severely impaired liver function. In some embodiments, the mean AUCt,ss t,ss The AUC is approximately 5000 pg / mL*h to approximately 10000 pg / mL*h. In some embodiments, the average AUC is... t,ssThe dosage is approximately 5000 pg / mL*h to approximately 7500 pg / mL*h. In some embodiments, liver function in human subjects is classified using a Child-Pugh score. In some embodiments, administration is by inhalation. In some embodiments, inhalation is by nebulizer. In some embodiments, encefentin is the free base of encefentin. In some embodiments, administration to human subjects is at least once, twice, or three times daily. In some embodiments, administration to human subjects is at least twice daily. In some embodiments, a therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof is approximately 2 mg to approximately 4 mg. In some embodiments, a therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof is 3 mg. In some embodiments, a therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof comprises a total daily dose of approximately 0.5 mg to approximately 10 mg of encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the total daily dose is approximately 5 mg to approximately 7 mg. In some embodiments, administration to human subjects comprises a first and a second daily dose. In some embodiments, the first dose comprises about 2 mg to about 4 mg of encefentin or a pharmaceutically acceptable salt thereof, and the second dose comprises about 2 mg to about 4 mg of encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the first and second doses comprise about 3 mg of encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the first dose is administered in the morning, and the second dose is administered in the evening. In some embodiments, the first dose is administered within three hours after the human subject wakes up, and the second dose is administered within three hours before the human subject goes to sleep. In some embodiments, the first and second doses are administered to the human subject about 10 to about 14 hours apart. In some embodiments, administration to the human subject is twice daily for at least 8 weeks. In some embodiments, administration to the human subject is twice daily for at least 16 weeks. In some embodiments, administration to the human subject is twice daily for at least 24 weeks. In some embodiments, the liquid pharmaceutical composition comprises a suspension of encefentin granules containing encefentin or a pharmaceutically acceptable salt thereof in a diluent. In some embodiments, encefentin granules contain at least 95% by weight encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, encefentin granules contain at least 95% by weight encefentin free base. In some embodiments, encefentin is in crystalline solid form, the crystalline solid consisting of more than 99% by weight encefentin free base, at least 95% being in the polymorphic form of thermodynamically stable polymorph (I) of encefentin free base, said thermodynamically stable polymorph (I) having the structural parameters obtained by single-crystal analysis as shown in Table 1.

[0008] Table 1 wavelength 0.71073 Å Crystal system Triclinic crystal system Space Group P-1 Cell size a = 8.1246(4)Å α = 91.583（4）° b = 11.4573 (5) Å ß =90.299（4）° c = 13.2398(6)Å γ = 99.628(4)° volume <![CDATA[1214.56(10)Å 3 ]]> Z 2 In some embodiments, encefentin granules contain about 0% to about 0.6% by weight of 1,3-bis(2-(2-(trimethylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (BMIQU) relative to the total weight of encefentin or its pharmaceutically acceptable salts. In some embodiments, encefentin granules contain about 0% to about 0.5% by weight of a biuret impurity of formula (A) relative to the total weight of encefentin or its pharmaceutically acceptable salts. .

[0009] In some embodiments, the encefentin granules contain about 0% to about 0.3% by weight of biuret impurities relative to the total weight of encefentin or its pharmaceutically acceptable salts. In some embodiments, the encefentin granules contain about 0.01% to about 0.3% by weight of BMIQU relative to the total weight of encefentin or its pharmaceutically acceptable salts. In some embodiments, the liquid pharmaceutical composition comprises: (a) encefentin granules; (b) a buffer; (c) one or more surfactants; and (d) a tonic modulator. In some embodiments, the liquid pharmaceutical composition comprises: (a) encefentin granules at a concentration of about 1 mg / mL to about 1.4 mg / mL; (b) a buffer at a concentration of about 1 mg / mL to about 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) a tonic modulator at a concentration of about 5 mg / mL to about 10 mg / mL. In some embodiments, the liquid pharmaceutical composition comprises: (a) encefentin granules at a concentration of about 1 mg / mL to about 1.4 mg / mL; (b) polysorbate 20 (Tween20) at a concentration of about 0.3 mg / mL to about 0.7 mg / mL; (c) sorbitan monolaurate (Span 20) at a concentration of 0 mg / mL to about 0.1 mg / mL; (d) sodium dihydrogen phosphate dihydrate at a concentration of about 0.5 mg / mL to about 1 mg / mL; (e) disodium hydrogen phosphate dihydrate at a concentration of about 0.5 mg / mL to about 1 mg / mL; and (f) sodium chloride at a concentration of about 5 mg / mL to about 10 mg / mL. In some embodiments, the liquid pharmaceutical composition comprises: (a) encefentin granules at a concentration of 1.2 mg / mL; (b) polysorbate 20 (Tween 20) at a concentration of 0.5 mg / mL; (c) sorbitan monolaurate (Span 20) at a concentration of 0.05 mg / mL; (d) sodium dihydrogen phosphate dihydrate at a concentration of 0.744 mg / mL; (e) disodium hydrogen phosphate dihydrate at a concentration of 0.853 mg / mL; and (f) sodium chloride at a concentration of 8.6 mg / mL. In some embodiments, the total weight of encefentin or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical composition is from about 2.7 mg to about 3.3 mg. In some embodiments, encefentin or a pharmaceutically acceptable salt thereof is used in combination with a muscarinic receptor antagonist, a β-adrenergic receptor agonist, or an inhaled corticosteroid. In some embodiments, the COPD is moderate COPD. In some embodiments, the COPD is severe COPD. This article provides for the use of any of the methods described herein for the treatment of COPD in human subjects. Attached Figure Description

[0010] The novel features of this disclosure are particularly set forth in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description (which illustrates exemplary embodiments utilizing the principles of this disclosure) and the accompanying drawings (also referred to herein as “Figure” and “FIG.”), in which: Figure 1A The predicted AUC was shown in COPD subjects with normal to moderately impaired renal function, and Figure 1B This shows the predicted C in COPD subjects with normal to moderately impaired renal function. max Encerfentin blood concentrations (median and 90% prediction range).

[0011] Figure 2 The simulated enstatin concentration-time curves at steady state are shown in COPD subjects with normal renal function, mild renal impairment, and moderate renal impairment.

[0012] Figure 3 The AUC is shown for subjects with healthy liver function, moderate liver damage, or severe liver damage. tau,ss Encerfentin blood concentration. Detailed Implementation

[0013] Some definitions As used herein and in the appended claims, unless the context clearly indicates otherwise, the singular forms “an,” “a,” and “the / described” include plural indicators. Thus, for example, reference to “reagent” includes a variety of such reagents. When a range is used herein for physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), it is contemplated to include all combinations and sub-combinations of the range, as well as specific embodiments thereof. When referring to a number or numerical range, the term “about” means that the number or numerical range mentioned is an approximation within experimental variability (or within statistical experimental error), and therefore the number or numerical range may vary between 1% and 15% of said number or numerical range. When referring to two numbers or ranges, the term “substantially identical” means that the numbers or ranges are within 1% to 15% of each other. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude. Embodiments of any material composition, composition, method, or process, etc., described herein may be “consisting of the described features” or “substantially composed of the described features.”

[0014] As used herein, unless otherwise stated, “%” or “percentage” as used herein means a percentage by weight (e.g., w / w%), a percentage by volume (e.g., v / v%), or a mole percentage (e.g., moles / moles%). Preferably, as used herein, “%” or “percentage” means a percentage by weight (e.g., w / w%).

[0015] As used herein, the terms “treat,” “treating,” or “treatment” include reducing, alleviating, eliminating, relieving, managing, lessening, or diminishing symptoms associated with a disease, disease state, condition, or indication (e.g., as provided herein) in chronic or acute treatment settings. Additionally, treatment of a disease or disease state as described herein includes disclosures of the use of such compounds or compositions for treating such diseases, disease states, conditions, or indications.

[0016] Valley value lung function During maintenance therapy, lung function in COPD patients typically follows a cycle. Lung function in COPD can be measured by determining the patient's forced expiratory volume in one second (FEV1). Improvements in lung function can be achieved within a period following drug administration, peaking at a certain point after drug administration. The patient's lung function then declines towards trough lung function: the lowest point in the lung function cycle during maintenance therapy. Trough lung function generally occurs shortly before the next administration of maintenance therapy medication. For example, for twice-daily (morning and evening) maintenance therapy, trough lung function typically occurs immediately before the morning dose (morning trough lung function) and the evening dose (evening trough lung function).

[0017] The trough lung function achieved during maintenance therapy can have a significant impact on the symptoms and / or quality of life of COPD subjects. Trough lung function effectively represents the worst lung function at a stage during maintenance therapy. For twice-daily dosing, the morning trough lung function often coincides with the patient's sleep time. This means that patients may have poor lung function during certain nighttime periods, disrupting their sleep (e.g., due to limited oxygen intake) and leading to fatigue, thus reducing their quality of life. This is indeed the case in some implementations, in COPD subjects who already have disturbed sleep, for example, due to comorbidities such as sleep disturbances and sleep disturbances.

[0018] If trough lung function improves, COPD symptoms can be accompanied by a more sustained improvement in quality of life. Improvements in trough lung function can be beneficial in subjects already susceptible to sleep disturbances. While many medications are publicly available for treating COPD, they are not all equally effective in improving trough lung function, particularly morning trough lung function. For subjects whose specific treatment expectation is to optimize the therapeutic effect of drug intervention, administering a specific medication that is effective in improving trough lung function would be clinically advantageous.

[0019] In some implementations, entifene effectively increases trough lung function in subjects with or without COPD. In some cases, when used as maintenance therapy, entifene effectively increases trough lung function in subjects with COPD. In some implementations, entifene can improve morning trough lung function in COPD subjects, which can be beneficial for COPD subjects who are susceptible to sleep disturbances, for example, due to the presence of comorbidities affecting sleep.

[0020] acute exacerbation of COPD In some cases, subjects with COPD also experience occasional, transient exacerbations of their symptoms (known as COPD exacerbations). COPD exacerbations typically involve increased shortness of breath (dyspnea), excessive mucus production (increased sputum volume), altered mucus color (purulent sputum), and / or increased cough. In some cases, the methods described in this article for reducing COPD exacerbations (e.g., by administration of enstatin) improve dyspnea. In some cases, the methods described in this article for reducing COPD exacerbations (e.g., by administration of enstatin) improve excessive mucus production. In some cases, the methods described in this article for reducing COPD exacerbations (e.g., by administration of enstatin) also reduce cough frequency.

[0021] In some cases, such as when a subject has not received a pharmaceutical composition as described elsewhere in this document (e.g., containing enstatin), the methods described herein for reducing acute exacerbations of COPD (e.g., by administering a pharmaceutical composition containing enstatin) reduce cough frequency by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70%). In some cases, such as when a subject has not received a pharmaceutical composition as described elsewhere in this document (e.g., containing enstatin), the methods described herein for reducing acute exacerbations of COPD (e.g., by administering a pharmaceutical composition containing enstatin) reduce cough frequency by up to 95% (e.g., up to 90%, up to 80%, up to 70%, up to 60%, or up to 50%). In some embodiments, administration of the pharmaceutical composition described herein (e.g., containing enstatin) to a subject reduces acute exacerbations of COPD by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70%.

[0022] In some cases, certain patient groups are particularly vulnerable to COPD exacerbations. In some cases, this includes subjects with other respiratory conditions such as asthma and subjects with allergic conditions. Subjects vulnerable to COPD exacerbations have typically experienced a previous COPD exacerbation. In some implementations, the patient group particularly vulnerable to COPD exacerbations includes subjects with asthma. In some implementations, the patient group particularly vulnerable to COPD exacerbations includes subjects with allergic conditions.

[0023] In some cases, COPD exacerbations can be severe and limit the quality of life for individuals with COPD. Not all medications publicly available for treating COPD are equally effective in reducing the severity and / or frequency of COPD exacerbations, or in shortening the time to the first COPD exacerbation. When there is a specific clinical need to manage such exacerbations, the use of COPD medications that effectively reduce the severity and / or frequency of COPD exacerbations may be advantageous.

[0024] In some implementations, enstatin has been highly effective in reducing the frequency and / or severity of COPD exacerbations in subjects with COPD. In particular, enstatin has been found to cause a more significant reduction in COPD exacerbations compared to many known treatments for COPD.

[0025] COPD severity The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classifies COPD into four distinct stages: mild COPD, moderate COPD, severe COPD, or very severe COPD. 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.

[0026] In some implementations, the COPD stages mentioned above can be classified as described below, where FVC is forced vital capacity. In some implementations, mild COPD is classified as FEV1 / FVC < 0.7 and FEV1 ≥ 80% of predicted value. In some implementations, moderate COPD is classified as FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80% of predicted value. In some implementations, severe COPD is classified as FEV1 / FVC < 0.7 and 30% ≤ FEV1 < 50% of predicted value. In some implementations, very severe COPD is classified as FEV1 / FVC < 0.7 and FEV1 < 30% of predicted value.

[0027] In some implementations, the subject's actual FEV1 is compared to a predicted FEV1 value based on factors such as the subject's age and height. These predicted 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 Respir CritCare. 1999;159:179-187). In some cases, an example of a formula for calculating a subject's predicted FEV1 (in L) is as follows, 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 can be used to determine the severity of COPD in patients and are measured by spirometry performed 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).

[0028] In some implementations, such as those used herein, FEV1 and FVC are determined as described in the article Standardisation of spirometry, Eur J 2005; 26; 319-338.

[0029] In some embodiments, a subject can be identified as having moderate COPD by measuring an FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80% of the predicted FEV1 value, wherein FEV1 is the forced expiratory volume in one second and FVC is the forced vital capacity, if measured between 15 and 30 minutes after the dose of a bronchodilator, optionally wherein the bronchodilator is salbutamol. In some embodiments, a subject can be identified as having severe COPD by measuring an FEV1 / FVC < 0.7 and 30% ≤ FEV1 < 50% of the predicted FEV1 value, wherein FEV1 is the forced expiratory volume in one second and FVC is the forced vital capacity, if measured between 15 and 30 minutes after the dose of a bronchodilator, optionally wherein the bronchodilator is salbutamol. The determination of the subject's COPD severity can be performed at least one day before the first administration of a compound (e.g., encefentin). The severity of COPD in a subject can be determined at least one week before the first administration of encefentanil (e.g., or a pharmaceutical composition containing encefentanil).

[0030] In some cases, as used in this paper, FEV1 and FVC are determined as described in the article Standardization of Spirometry, Eur J 2005; 26; 319-338.

[0031] In some cases, enstatin is effective in treating all forms of COPD. In some cases, enstatin is effective in treating moderate COPD. In some cases, enstatin is effective in treating mild COPD. In some cases, enstatin is effective in treating severe COPD. In some cases, enstatin is effective in treating very severe COPD. In some cases, inhaled enstatin administration has been found to result in a significant increase in FEV1 (forced expiratory volume in one second) in subjects with moderate COPD.

[0032] In some cases, depending on the apparent clearance of encefentin, the pharmaceutical compositions described herein (e.g., those containing encefentin) may provide different pharmacokinetic (PK) parameters. Apparent clearance can be affected by differences in renal or hepatic impairment. It is desirable to determine appropriate plasma concentrations of encefentin (e.g., due to potential changes in clearance) to provide to subjects with altered renal or hepatic impairment in order to broaden the potential patient population awaiting encefentin treatment.

[0033] Kidney and liver function In some cases, the pharmaceutical compositions provided herein (e.g., containing encefentin) are effective in treating COPD in individuals with varying levels of renal function. In some cases, the pharmaceutical compositions provided herein are effective in treating COPD in individuals with normal renal function. In some cases, the pharmaceutical compositions provided herein are effective in treating COPD in individuals with renal impairment. In some embodiments, renal impairment may include mild or moderate renal impairment. In some embodiments, encefentin is effective in treating COPD in patients with varying levels of renal impairment, with different pharmacokinetic (PK) parameters obtained in subjects with normal to mild renal impairment and subjects with moderate renal impairment, as described in Example 1. Changes in renal impairment may be associated with a decrease in the apparent clearance of encefentin and steady-state C max It is associated with an increase in AUC (exposure value).

[0034] In some embodiments, the pharmaceutical compositions provided herein are effective in treating COPD in individuals with varying levels of hepatic impairment, such as those described in Example 1. In some embodiments, the pharmaceutical compositions are effective in treating COPD in individuals with moderate hepatic impairment. In some embodiments, the pharmaceutical compositions are effective in treating COPD in individuals with severe hepatic impairment. While liver function can be a factor in clearance rates (e.g., of enstatin) in subjects, it has been found, as described in Example 1, that PK parameters, such as steady-state AUC, are not substantially different from each other regardless of the degree of hepatic impairment. In some cases, the PK parameters of subjects with hepatic impairment are not different from those of subjects without hepatic impairment.

[0035] The term "subject" as used herein may also be referred to as "patient." In any of the embodiments provided herein, the subject may be a human subject. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is 65 years of age or older. In some embodiments, the subject is less than 65 years of age. In some embodiments, the subject provided herein may be categorized into one or more subgroups. In some embodiments, the subgroup includes levels of renal impairment. In some embodiments, the subgroup includes normal renal function to mild renal impairment. In some embodiments, the subgroup includes moderate renal impairment. In some embodiments, the subgroup includes levels of hepatic impairment. In some embodiments, the subgroup includes normal liver function. In some embodiments, the subgroup includes moderate liver function. In some embodiments, the subgroup includes severe hepatic impairment. As described herein, the level of renal or hepatic impairment can alter the clearance rate of administered enstatin. Therefore, expected plasma concentrations are desired for individual subgroups of an individual (e.g., those individuals exhibiting altered enstatin clearance).

[0036] In some embodiments, the subjects described herein may take background medications. In some embodiments, the background medication is selected from one or more of long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA), and inhaled corticosteroids (ICS). In some embodiments, the background medication is a long-acting muscarinic antagonist (LAMA). In some embodiments, the background medication is a long-acting beta-agonist (LABA). In some embodiments, the background medication is an inhaled corticosteroid (ICS). In some embodiments, the subjects described herein do not take background medications, which are long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA), and inhaled corticosteroids (ICS).

[0037] Encerfentin pharmaceutical composition In some embodiments, this document provides pharmaceutical compositions comprising encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides pharmaceutical compositions comprising a free base of encefentin.

[0038] In any of the embodiments provided herein, the pharmaceutical composition may be a liquid pharmaceutical composition.

[0039] In some embodiments, the pharmaceutical composition is a suspension (e.g., a suspension containing granules of enstatin in a diluent). In some embodiments, the pharmaceutical composition is a dry powder. In some embodiments, the dry powder comprises granules containing the compound and granules of a carrier (e.g., lactose). In some embodiments, the dry powder is dispersed in a diluent, such as those described elsewhere herein.

[0040] In some embodiments, the pharmaceutical compositions provided herein are inhalable pharmaceutical compositions. In some embodiments, the inhalable pharmaceutical composition comprises a suspension of ensifine particles in a diluent, such as those described in other parts of this document.

[0041] In some embodiments, the pharmaceutical compositions provided herein comprise (e.g., encefentin) particles. In some embodiments, the particles comprise encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the particles comprise at least 90% by weight encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the particles comprise at least 95% by weight encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the particles comprise at least 97.5% by weight encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the particles comprise at least 98% by weight encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the particles comprise at least 99% by weight encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the particles comprise at least 99.2% by weight encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the particles consist of encefentin or a pharmaceutically acceptable salt thereof. In some embodiments, the particles comprise at least 90% by weight encefentin free base. In some embodiments, the granules contain at least 95% encefentin free base by weight. In some embodiments, the granules contain at least 97.5% encefentin free base by weight. In some embodiments, the granules contain at least 98% encefentin free base by weight. In some embodiments, the granules contain at least 99% encefentin free base by weight. In some embodiments, the granules contain at least 99.2% encefentin free base by weight. In some embodiments, the granules consist entirely of encefentin free base.

[0042] In some implementations, such as those used herein, particles containing encefentin may be referred to as "encefentin particles".

[0043] In some embodiments, the encefentin provided herein is in crystalline form. In some embodiments, at least 90% by weight of the encefentin is in the form of encefentin free base type I. In some embodiments, at least 90% of the particles contain encefentin free base type I. Encefentin free base type I is a crystalline polymorph of encefentin (crystalline polymorph type I), which typically has a powder X-ray diffraction pattern containing characteristic peaks at 10.1° and 12.9° ± 0.1° 2θ. As used herein, the value of °2θ can be measured using X-ray wavelengths of Cu Kα radiation (λ = 1.5406 Å). In some embodiments, the powder X-ray diffraction pattern of type I further contains characteristic peaks at 15.3° and 17.6° ± 0.1° 2θ. In some embodiments, the encefenstein type I may have a powder X-ray diffraction pattern containing at least five characteristic peaks selected from the following: 6.4°, 10.1°, 12.6°, 12.9°, 13.6°, 14.2°, 14.7°, 15.3°, 15.4°, 15.8°, 17.0°, 17.6°, 18.9°, 20.9°, 22.4°, 22.8°, and 28.7° ±0.1° 2θ. In some embodiments, the crystalline polymorph type I has a differential scanning calorimetry curve showing a maximum value at 248°C.

[0044] In some embodiments, the powder X-ray diffraction pattern of Encerfentin type I contains at least five (e.g., at least three, four, six, seven, or eight) characteristic peaks in 2θ selected from the following: about 6.4°, about 10.1°, about 12.6°, about 12.9°, about 13.6°, about 14.2°, about 14.7°, about 15.3°, about 15.4°, about 15.8°, about 17.0°, about 17.6°, about 18.9°, about 20.9°, about 22.4°, about 22.8°, and about 28.7°.

[0045] In some embodiments, the particles contain at least 98% by weight of encefenstein crystalline polymorph type I. In some embodiments, (e.g., encefenstein) the particles contain at least 99% by weight of encefenstein crystalline polymorph type I.

[0046] In some implementations, the Encefenstein crystalline polymorph type I has the following structural parameters obtained by single-crystal analysis: Wavelength 0.71073 Å Crystal system: triclinic Space group P-1 Cell size a = 8.1246 (4) Å α = 91.583 (4)° bb = 11.4573(5)Å ß=90.299(4)° cc = 13.2398(6)Å γ = 99.628(4)° Volume 1214.56 (10) Å 3 C 2.

[0047] In some cases, crystalline polymorph I is the most thermodynamically stable polymorph of encefentin and is also expected to have the longest shelf life. This advantage is expected to extend further to the potential shelf life of any commercial encefentin pharmaceutical product that includes stable crystalline polymorph I as an API. Furthermore, crystalline polymorph I is more conducive to the development of reproducible, homogeneous, micronized, dried solid powders of encefentin for certain pharmaceutical formulation applications, such as the formulation preparations described herein.

[0048] Impurity Overview Known processes for the production of encefentin have been found to be associated with undesirable impurity levels. For example, the process described in WO 00 / 58308 A1, which involves adding a urea group using an aqueous solution of sodium cyanate and hydrochloric acid, produces encefentin containing biuret impurities that are not easily removed. WO 2018 / 020249 A1 discusses several possible reagents that can be used to add the urea group in the final step of encefentin production, but does not provide a detailed discussion of the conditions for the final ureation step. It is desirable to utilize synthetic processes for the production of encefentin that produce a pharmaceutical substance with a favorable impurity profile without extensive purification and recrystallization, and particularly, where the pharmaceutical substance contains low levels of biuret impurities. In some cases, it has been found possible to produce encefentin with a favorable impurity profile, and particularly with low levels of biuret impurities, by a reaction comprising reacting an amine intermediate with 4-nitrobenzene chloroformate and ammonia in a solvent containing dichloromethane.

[0049] In some embodiments, the particles provided herein (e.g., Encefentin) comprise 1,3-bis(2-(2-(trimethylylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (BMIQU). In some embodiments, the structure of BMIQU is as follows: In some embodiments, the granules provided herein (e.g., Encefentanil) contain approximately 0% to 0.6% BMIQU by weight. In some embodiments, the granules contain at least approximately 0.005% BMIQU by weight. In some embodiments, the granules contain at least approximately 0.01% BMIQU by weight. In some embodiments, the granules contain at least approximately 0.1% BMIQU by weight. In some embodiments, the granules contain at most approximately 1% BMIQU by weight. In some embodiments, the granules contain at most approximately 0.6% BMIQU by weight. In some embodiments, the granules contain at most approximately 0.3% BMIQU by weight. In some embodiments, the granules contain approximately 0.01% to approximately 0.3% BMIQU by weight. In some embodiments, the granules contain approximately 0.3% to approximately 0.6% BMIQU by weight. In some embodiments, the granules contain BMIQU in an amount of about 0.02% to about 0.06% by weight. In some embodiments, the weight percentage is relative to the total weight of encefentanyl (e.g., free base). In some embodiments, the weight percentage is relative to the total weight of the granules.

[0050] In some embodiments, the particles provided herein (e.g., Encefentin) contain a biuret impurity of formula (A): (A) In some embodiments, (e.g., Encerfentin) the particles contain a biuret impurity of formula (A) in an amount of 0% to about 0.5% by weight. In some embodiments, the particles contain a biuret impurity of formula (A) in an amount of at least 0.01% by weight. In some embodiments, the particles contain a biuret impurity of formula (A) in an amount of at least 0.05% by weight. In some embodiments, the particles contain a biuret impurity of formula (A) in an amount of at least 0.1% by weight. In some embodiments, the particles contain a biuret impurity of formula (A) in an amount of at least 0.3% by weight. In some embodiments, the particles contain a biuret impurity of formula (A) in an amount of at most 0.7% by weight. In some embodiments, the particles contain a biuret impurity of formula (A) in an amount of at most 0.5% by weight. In some embodiments, the particles contain a biuret impurity of formula (A) in an amount of at most 0.3% by weight. In some embodiments, the particles contain at most 0.2% by weight of biuret impurity of formula (A). In some embodiments, the particles contain 0% to about 0.3% by weight of biuret impurity of formula (A). In some embodiments, the particles contain 0% to about 0.05% by weight of biuret impurity of formula (A). In some embodiments, the particles contain 0% to about 0.03% by weight of biuret impurity of formula (A). In some embodiments, the weight percentage is relative to the total weight of encefentin (e.g., free base). In some embodiments, the weight percentage is relative to the total weight of the particles.

[0051] In some embodiments, (e.g., Ensefentine) particles comprise 1-(2-(9-hydroxy-2-(trimethylimino)-10-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (9-demethyl impurity). In some embodiments, (e.g., Ensefentine) particles comprise 1-(2-(10-hydroxy-2-(trimethylimino)-9-methoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (10-demethyl impurity). In some embodiments, the particles comprise both 9-demethyl and 10-demethyl impurities. In some embodiments, the particles comprise either 9-demethyl or 10-demethyl impurities.

[0052] In some embodiments, the 9-demethylated impurity has the following structure: In some embodiments, the 10-demethylated impurity has the following structure: In some embodiments, the particles (e.g., encefentin) contain 0% to about 0.1% of 9-demethyl impurity by weight. In some embodiments, the particles contain at least 0.01% of 9-demethyl impurity by weight. In some embodiments, the particles contain at least 0.05% of 9-demethyl impurity by weight. In some embodiments, the particles contain at least 0.1% of 9-demethyl impurity by weight. In some embodiments, the particles contain at most 0.2% of 9-demethyl impurity by weight. In some embodiments, the particles contain 0.1% of 9-demethyl impurity by weight. In some embodiments, the particles contain about 0.01% to about 0.1% of 9-demethyl impurity by weight. In some embodiments, the particles contain about 0.01% to about 0.05% of 9-demethyl impurity by weight. In some embodiments, the weight percentage is relative to the total weight of encefentin (e.g., free base). In some implementations, the weight percentage is relative to the total weight of the particles.

[0053] In some embodiments, the particles (e.g., encefentin) contain 0% to about 0.1% by weight of 10-demethyl impurities. In some embodiments, the particles contain at least 0.01% by weight of 10-demethyl impurities. In some embodiments, the particles contain at least 0.05% by weight of 10-demethyl impurities. In some embodiments, the particles contain at least 0.1% by weight of 10-demethyl impurities. In some embodiments, the particles contain at most 0.2% by weight of 10-demethyl impurities. In some embodiments, the particles contain 0.1% by weight of 10-demethyl impurities. In some embodiments, the particles contain about 0.01% to about 0.1% by weight of 10-demethyl impurities. In some embodiments, the particles contain about 0.01% to about 0.05% by weight of 10-demethyl impurities. In some embodiments, the weight percentage is relative to the total weight of encefentin (e.g., free base). In some implementations, the weight percentage is relative to the total weight of the particles.

[0054] In some embodiments, (e.g., encefentin) the particles comprise (E)-2-(trimethylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinoline-4-one (compound (I)). In some embodiments, (e.g., encefentin) the particles comprise (E)-3-(2-aminoethyl)-2-(trimethylimino)-9,10-dimethoxy-2,3,6,7-tetrahydro-4H-pyrimido[6,1-a]isoquinoline-4-one (compound (IV)). In some embodiments, the particles comprise both compound (I) and compound (IV). In some embodiments, the particles comprise either compound (I) or compound (IV).

[0055] In some embodiments, the structure of compound (I) is as follows: In some implementations, the structure of compound (IV) is as follows: In some embodiments, (e.g., encefentin) the particles contain 0% to about 0.04% of compound (I) by weight. In some embodiments, the particles contain at least 0.01% of compound (I) by weight. In some embodiments, the particles contain at least 0.02% of compound (I) by weight. In some embodiments, the particles contain at most 0.05% of compound (I) by weight. In some embodiments, the particles contain at most 0.04% of compound (I) by weight. In some embodiments, (e.g., encefentin) the particles contain 0% to about 0.04% of compound (IV) by weight. In some embodiments, the particles contain at least 0.01% of compound (IV) by weight. In some embodiments, the particles contain at least 0.02% of compound (IV) by weight. In some embodiments, the particles contain at most 0.05% of compound (IV) by weight. In some embodiments, the particles contain at most 0.04% of compound (IV) by weight. In some embodiments, the particles do not contain compound (I). In some embodiments, the particles do not contain compound (IV). In some embodiments, the particles do not contain compound (I) or compound (IV). In some embodiments (e.g., encefentin), the particles contain a total of 0% to about 0.04% of compound (I) and compound (IV) by weight. In some embodiments, the particles contain a total of at least 0.01% of compound (I) and compound (IV) by weight. In some embodiments, the particles contain a total of at least 0.02% of compound (I) and compound (IV) by weight. In some embodiments, the particles contain a total of up to 0.05% of compound (I) and compound (IV) by weight. In some embodiments, the particles contain a total of up to 0.04% of compound (I) and compound (IV) by weight. In some embodiments, the weight percentage is relative to the total weight of encefentin (e.g., free base). In some embodiments, the weight percentage is relative to the total weight of the particles.

[0056] In some embodiments, BMIQU, biuret impurities, 9-demethyl impurities, 10-demethyl impurities, compound (I) and compound (IV) (if present) may optionally be present in the form of salts. In some embodiments, BMIQU, biuret impurities, 9-demethyl impurities, 10-demethyl impurities, compound (I) and compound (IV) are present in the form of free bases.

[0057] In some embodiments, the particles provided herein (e.g., encefentin) comprise encefentin (e.g., encefentin free base (e.g., in crystalline form I)), BMIQU, biuret impurity, 9-demethyl impurity, and 10-demethyl impurity. In some embodiments, the particles provided herein (e.g., encefentin) consist of encefentin (e.g., encefentin free base (e.g., in crystalline form I)), BMIQU, biuret impurity, 9-demethyl impurity, and 10-demethyl impurity.

[0058] In some embodiments, the particles provided herein (e.g., encefentin) comprise about 99.4% to about 99.9% by weight of encefentin, about 0.01% to about 0.3% by weight of BMIQU, about 0% to about 0.1% by weight of biuret impurities, about 0.01% to about 0.2% by weight of 9-demethyl impurities, and about 0.01% to about 0.2% by weight of 10-demethyl impurities, wherein the weight percentages are relative to the total weight of the particles.

[0059] In some embodiments, the particles provided herein (e.g., encefentin) comprise about 99.5% to about 99.9% by weight of encefentin, about 0.02% to about 0.1% by weight of BMIQU, about 0% to about 0.04% by weight of biuret impurities, about 0.01% to about 0.1% by weight of 9-demethyl impurities, and about 0.01% to about 0.1% by weight of 10-demethyl impurities, wherein the weight percentages are relative to the total weight of the particles.

[0060] In some embodiments, the particles provided herein (e.g., encefentin) consist of: about 99.6% to about 99.9% encefentin by weight, about 0.02% to about 0.1% BMIQU by weight, about 0% to about 0.04% biuret impurity by weight, about 0.01% to about 0.1% 9-demethyl impurity by weight, and about 0.01% to about 0.1% 10-demethyl impurity by weight, wherein the weight percentages are relative to the total weight of the particles.

[0061] In some embodiments, this document provides particles comprising encefentin (e.g., encefentin free base). In some embodiments, the particles have a particle size distribution of Dv50 from about 0.5 µm to about 5.0 µm. In some embodiments, the particles comprise Dv50 from about 1.0 µm to about 2.0 µm. In some embodiments, the particles comprise Dv90 from about 1.8 µm to about 2 µm. In some embodiments, the particles comprise Dv90 from about 2.5 µm to about 6.0 µm. In some embodiments, the particles comprise Dv90 from about 2.8 µm to about 4.2 µm. In some embodiments, the particles comprise Dv10 from about 0.2 µm to about 1.0 µm. In some embodiments, the particles comprise Dv10 from about 0.4 µm to about 0.6 µm. In some embodiments, the particles comprise Dv10 from about 0.4 µm to about 0.6 µm and Dv90 from about 2.8 µm to about 4.2 µm. In some embodiments, the particles contain Dv90 of no more than 4.5 µm. In some embodiments, the particles contain Dv90 of about 2, 2.1, 2.2, 2.3, 2.5, 2.5, or 2.6 µm.

[0062] In some embodiments, particle size is described herein by reference to a Dv50 value, which is the median particle size of the volume distribution. Thus, half the volume of particles has a diameter smaller than the Dv50 value, and half the volume of particles has a diameter larger than the Dv50 value. Similarly, in some embodiments, particle size is described herein by its Dv90 or Dv10 value. Those skilled in the art will understand that these are well-known parameters used to describe particle size distribution.

[0063] The technique described herein for measuring particle size (e.g., Dv10, Dv50, Dv90 values) can be laser diffraction. The particle size distribution of particles containing encefentin can be measured using laser diffraction with a wet powder dispersion system. In some cases, the particle size distribution can be measured using laser diffraction with a Malvern Spraytec in conjunction with a wet dispersion cell. In some cases, the instrument parameters for the Malvern Spraytec are as follows: • Granules - Standard opaque granules; • Particle refractive index - 1.50; • Refractive index (imaginary part) - 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; • Light blocking effect: -20% - 30%; • Dispersant - 1% deionized aqueous solution of polysorbate 20.

[0064] Particle size distribution can be measured using laser diffraction with a 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 • Dispersant name: 0.02% aqueous solution of polysorbate 20 • Refractive index: 1.330 Mixer; 1000 rpm • Sample measurement: 10 seconds • Light blocking: 10-20% The particles described herein may contain encefentin (e.g., encefentin free base). In some embodiments, the particles contain at least 90% by weight of encefentin free base relative to the total weight of the particles. In some embodiments, the particles contain at least 95% by weight of encefentin free base. In some embodiments, the particles contain at least 97% by weight of encefentin free base. In some embodiments, the particles contain at least 99% by weight of encefentin free base. In some embodiments, the particles contain at least 99.5% by weight of encefentin free base. In some cases, the particles consist entirely of encefentin.

[0065] According to those skilled in the art, particles containing encefentin (e.g., encefentin free base) can be present in the pharmaceutical composition at any suitable concentration. In some embodiments, particles containing encefentin are present in the pharmaceutical composition at a concentration of about 0.1 mg / mL to about 5.0 mg / mL. In some embodiments, particles are present in the pharmaceutical composition at a concentration of about 0.1 mg / mL to about 2.5 mg / mL. In some embodiments, particles are present in the pharmaceutical composition at a concentration of about 1.0 mg / mL to about 2.0 mg / mL. In some embodiments, particles containing encefentin are present in the pharmaceutical composition at a concentration of (e.g., about) 1.2 mg / mL.

[0066] In some embodiments, the concentration of encefentin or a pharmaceutically acceptable salt thereof (e.g., encefentin free base) in the pharmaceutical composition is at least 0.8 mg / mL. In some embodiments, the concentration of encefentin or a pharmaceutically acceptable salt thereof (e.g., encefentin 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 encefentin or a pharmaceutically acceptable salt thereof (e.g., encefentin free base) is at most 1.5 mg / mL. The concentration of encefentin or a pharmaceutically acceptable salt thereof (e.g., encefentin free base) is at most 1.4 mg / mL (e.g., 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 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 pharmaceutical composition is (e.g., about) 1.2 mg / mL.

[0067] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more tension modifiers, one or more buffers, and one or more surfactants. In some embodiments, the pharmaceutical compositions further comprise one or more tension modifiers. In some embodiments, the pharmaceutical compositions further comprise one or more buffers. In some embodiments, the pharmaceutical compositions further comprise one or more surfactants.

[0068] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more tension modifiers. In some embodiments, the tension modifier comprises sodium chloride. In some embodiments, the tension modifier (e.g., sodium chloride) is present in the 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 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 concentrations 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 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 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 pharmaceutical composition at a concentration of (e.g., about) 8.6 mg / mL.

[0069] In some embodiments, the 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 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 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, the buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the 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, the buffer (e.g., sodium dihydrogen phosphate dihydrate and / or disodium hydrogen phosphate dihydrate) is present in the pharmaceutical composition at a concentration of about 1.5 mg / mL to about 1.7 mg / mL.

[0070] In some embodiments, the 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 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 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 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 pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration of about 0.7 mg / mL. In some embodiments, the pharmaceutical composition comprises sodium dihydrogen phosphate dihydrate at a concentration of (e.g., about) 0.744 mg / mL.

[0071] In some embodiments, the pharmaceutical composition comprises disodium hydrogen 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, 0.7 mg / mL). In some embodiments, the pharmaceutical composition comprises disodium hydrogen 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). In some embodiments, the pharmaceutical composition comprises disodium hydrogen phosphate dihydrate at a concentration of about 0.7 mg / mL to about 1 mg / mL. In some embodiments, the pharmaceutical composition comprises disodium hydrogen phosphate dihydrate at a concentration of about 0.8 mg / mL to about 0.9 mg / mL. In some embodiments, the pharmaceutical composition comprises disodium hydrogen phosphate dihydrate at a concentration of about 0.8 mg / mL. In some embodiments, the pharmaceutical composition comprises disodium hydrogen phosphate dihydrate at a concentration of about 0.9 mg / mL. In some embodiments, the pharmaceutical composition comprises disodium hydrogen phosphate dihydrate at a concentration of (e.g., about) 0.853 mg / mL.

[0072] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more surfactants. In some embodiments, one or more surfactants comprise lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG 300, PEG 600, PEG1000, Brij 30, Brij 35, Brij 56, Brij 76, and Brij 97), polypropylene glycol (e.g., PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ether, polyoxyethylene glycol alkylphenol ethers, glyceryl alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (e.g., 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 80)). 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 surfactants), polyvinylpyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate, and polyethoxylated tallow amine (POEA). In some embodiments, one or more embodiments comprise polysorbate and / or alkyl sorbitan esters. In some embodiments, one or more surfactants 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). In some embodiments, one or more surfactants comprise sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), or sorbitan trioleate (Span 85). In some embodiments, the pharmaceutical composition comprises polysorbate 20 (Tween 20) and / or sorbitan monolaurate (Span 20). In some cases, the surfactant acts as a wetting agent in the pharmaceutical composition described herein (e.g., liquid).

[0073] In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of 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). In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration 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 pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.3 mg / mL to about 0.7 mg / mL. In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.01 mg / mL to 2 mg / mL. In some embodiments, the pharmaceutical composition comprises one or more 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 pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.5 mg / mL. In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of about 0.6 mg / mL. In some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., polysorbate 20 and / or sorbitan monolaurate) at a concentration of (e.g., about) 0.55 mg / mL.

[0074] In some embodiments, the pharmaceutical composition comprises polysorbate 20 (e.g., Tween 20) at a concentration 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 pharmaceutical composition comprises polysorbate 20 (e.g., Tween 20) at a concentration 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 pharmaceutical composition comprises polysorbate 20 (e.g., Tween 20) at a concentration of about 0.3 mg / mL to about 0.7 mg / mL. In some embodiments, the pharmaceutical composition comprises polysorbate 20 (e.g., Tween 20) at a concentration of about 0.4 mg / mL to about 0.6 mg / mL. In some embodiments, the pharmaceutical composition comprises polysorbate 20 (e.g., Tween 20) at a concentration of about 0.5 mg / mL.

[0075] In some embodiments, the pharmaceutical composition comprises sorbitan monolaurate (Span 20) at a concentration of at least 0.01 mg / mL (e.g., 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL). In some embodiments, the pharmaceutical composition comprises sorbitan monolaurate (Span 20) at 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). In some embodiments, the pharmaceutical composition comprises sorbitan monolaurate (Span 20) at a concentration of about 0.03 mg / mL to about 0.07 mg / mL. In some embodiments, the pharmaceutical composition comprises sorbitan monolaurate (Span 20) at a concentration of about 0.04 mg / mL to about 0.06 mg / mL. In some embodiments, the pharmaceutical composition comprises sorbitol monolaurate (Span20) at a concentration of (e.g., about) 0.05 mg / mL.

[0076] In some embodiments, the pharmaceutical compositions provided herein comprise: a. water; b. Particles consisting of encefentin free base at a concentration of about 0.1 mg / mL to about 20 mg / mL; c. One or more tension modifiers at a concentration of about 1.0 mg / mL to about 15 mg / mL; d. One or more buffers with a total concentration of about 0.1 mg / mL to about 4.0 mg / mL; and e. One or more surfactants with a total concentration of about 0.05 mg / mL to about 3 mg / mL.

[0077] In some embodiments, the liquid pharmaceutical compositions provided herein comprise: a. water; b. Particles consisting of encefentin free base at a concentration of about 0.5 mg / mL to about 6 mg / mL; c. Sodium chloride at a concentration of about 5 mg / mL to about 12 mg / mL; d. Sodium dihydrogen phosphate dihydrate at a concentration of about 0.3 mg / mL to about 2 mg / mL; e. Disodium hydrogen phosphate dihydrate at a concentration of about 0.3 mg / mL to about 2 mg / mL; and f. Dehydrated sorbitan monolaurate at a concentration of about 0.01 mg / mL to about 0.5 mg / mL.

[0078] In some embodiments, the pharmaceutical composition described herein is provided in an ampoule, for example, for administration by inhalation using a nebulizer. In some embodiments, the ampoule comprises an encefentin granule suspension as described herein. In some embodiments, the ampoule comprises about 2.6 mL of the pharmaceutical composition. In some embodiments, the ampoule comprises at least 3 mg of encefentin (e.g., encefentin free base). In some embodiments, the ampoule comprises about 3.1 mg of encefentin. In some embodiments, the ampoule is a low-density polyethylene (LDPE) ampoule.

[0079] In some cases, the pharmaceutical compositions described herein may be referred to as encefentin compositions.

[0080] In some embodiments, encefentin or a pharmaceutically acceptable salt thereof, as described herein, may be used in combination with a second active agent. In some embodiments, encefentin or a pharmaceutically acceptable salt thereof may be administered separately from or concurrently with the second active agent. In some embodiments, the subject may already be taking the second active agent as background treatment for COPD. Alternatively, treatment with the second active agent may be initiated substantially simultaneously with treatment with encefentin. Encefentin and the second active agent may be administered in a fixed combination.

[0081] In some embodiments, the second active agent, as provided herein, is a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid. In some embodiments, encefenstein or a pharmaceutically acceptable salt thereof may be used in combination with a muscarinic receptor antagonist, a beta-adrenergic receptor agonist, or an inhaled corticosteroid. The second active agent may be a long-acting muscarinic receptor antagonist (LAMA) or a long-acting beta-adrenergic receptor agonist (LABA). In some embodiments, the second active agent is a muscarinic receptor antagonist. In some embodiments, the second active agent is a beta-adrenergic receptor agonist. In some embodiments, the second active agent is an inhaled corticosteroid.

[0082] In some embodiments, non-limiting examples of LAMA include adefenac, darobromide, tiotropium bromide, glycopyrronium bromide, and umemetium bromide. In some embodiments, non-limiting examples of LABA include salmeterol, formoterol, indacaterol, vilanterol, olodaterol, abedaterol, and carmoterol. In some embodiments, non-limiting examples of inhaled corticosteroids include beclomethasone, budesonide, fluticasone propionate, ciroxonide, mometasone, and fluticasone furoate.

[0083] In some implementation schemes, the subjects described herein may use a β-agonist such as salbutamol as an emergency treatment.

[0084] COPD treatment This document provides methods for treating chronic obstructive pulmonary disease (COPD) (e.g., COPD of varying severity), such as those provided in other parts of this document. In some embodiments, the methods provided herein include administering (e.g., liquid) a pharmaceutical composition, such as those provided in other parts of this document, to a subject in need of this treatment, comprising a therapeutically effective amount of enstatin. In some embodiments, the methods provided herein include administering (e.g., a therapeutically effective amount) enstatin to a subject in need of this treatment.

[0085] In some embodiments, the methods provided herein are effective in treating mild, moderate, severe, or very severe COPD. In some embodiments, the methods provided herein are effective in treating mild COPD. In some embodiments, the methods provided herein are effective in treating moderate COPD. In some embodiments, the methods provided herein are effective in treating severe COPD. In some embodiments, the methods provided herein are effective in treating very severe COPD. In some embodiments, the methods provided herein are effective in treating moderate or severe COPD, such as moderate or severe COPD (e.g., classified as described in other sections of this document).

[0086] COPD subgroups In some implementations, this document provides methods for treating COPD in specific subgroups of populations that may exhibit different clearance rates of the administered ensifine.

[0087] C max AUC 0-tau and T max These are pharmacokinetic parameters well-known to technicians. C max T is the maximum concentration of the compound reached in the plasma after administration. max C was observed at that location. max The AUC is the area under the curve of the plasma concentration of a compound as a function of time following administration, over a given period. 0-tau This is the AUC from the time of administration to the end of the dosing period (which can be, for example, 8 hours, 12 hours, or 24 hours). As used herein, tau is typically 12 hours, and AUC 0-tau For AUC 0-12h In some cases, tau is 4 hours.

[0088] In some embodiments, enstatin effectively increases lung function (e.g., FEV1) in subjects with mild or moderate COPD. In some embodiments, enstatin effectively increases lung function in subjects with severe or very severe COPD. In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides at least 0.08 L (80 mL) of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides at least 0.09 L (e.g., 0.1 L, 0.11 L) of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides up to 0.14 L (140 mL) of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides up to 0.13 L (e.g., 0.12 L, 0.11 L) of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides approximately 0.08 L to approximately 0.14 L of FEV1 AUC.0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides approximately 0.09 L to approximately 0.13 L of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides approximately 0.11 L (110 mL) of FEV1 AUC. 0-12h (For example, 12 weeks after application).

[0089] In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides at least 0.03 L (30 mL) of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with severe or profound COPD provides 0.04 L (e.g., 0.05 L, 0.06 L) of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with severe or profound COPD provides up to 0.09 L (e.g., 0.08 L, 0.07 L, 0.06 L) of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with severe or profound COPD provides approximately 0.03 L to approximately 0.09 L of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides approximately 0.05 L to approximately 0.07 L of FEV1 AUC. 0-12h (For example, after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides approximately 0.06 L (60 mL) of FEV1 AUC. 0-12h (For example, 12 weeks after application).

[0090] In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides a change of at least 0.14 L (e.g., 140 mL) from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides a change of at least 0.15 L (e.g., 0.16 L, 0.17 L) from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides a change of up to 0.2 L (e.g., 0.19 L, 0.18 L, 0.17 L) from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides a change of about 0.14 L to about 0.2 L from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides a change of about 0.15 L to about 0.18 L from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides a change of about 0.17 L (170 mL) from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration).

[0091] In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides at least 0.08 L (80 mL) of change from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides at least 0.09 L (e.g., 0.1 L, 0.11 L) of change from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides up to 0.15 L (150 mL) of change from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides a change of up to 0.15 L (e.g., 0.14 L, 0.13 L, or 0.12 L) from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides a change of about 0.08 L to about 0.15 L from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides a change of about 0.1 L to about 0.14 L from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration). In some implementations, administration of a drug composition (e.g., containing encefentanyl) to a subject with severe or very severe COPD provides approximately 0.11 L of change from baseline FEV1 to peak FEV1 (e.g., after 12 weeks of administration).

[0092] In some implementations, the change in FEV1 from baseline to peak is at least 30% higher in subjects with mild or moderate COPD than in subjects with severe or very severe COPD. In some implementations, the change in FEV1 from baseline to peak is at least 40% higher in subjects with mild or moderate COPD than in subjects with severe or very severe COPD. In some implementations, the change in FEV1 from baseline to peak is about 40% to about 60% higher in subjects with mild or moderate COPD than in subjects with severe or very severe COPD. In some implementations, the change in FEV1 from baseline to peak is about 55% higher in subjects with mild or moderate COPD than in subjects with severe or very severe COPD.

[0093] In some implementations, subjects with severe or profound COPD experience at least a 30% higher change in baseline FEV1 to peak FEV1 compared to subjects with mild or moderate COPD. In some implementations, subjects with severe or profound COPD experience at least a 40% higher change in baseline FEV1 compared to subjects with mild or moderate COPD. In some implementations, subjects with severe or profound COPD experience approximately 40% to approximately 60% higher change in baseline FEV1 compared to subjects with mild or moderate COPD. In some implementations, subjects with severe or profound COPD experience approximately 55% higher change in baseline FEV1 compared to subjects with mild or moderate COPD.

[0094] In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides at least 0.13 L (130 mL) of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides at least 0.14 L (e.g., 0.15 L, 0.16 L) of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides up to 0.19 L (190 mL) of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides up to 0.18 L (e.g., 0.17 L, 0.16 L) of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides approximately 0.13 L to approximately 0.19 L of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides approximately 0.14 L to approximately 0.18 L of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with mild or moderate COPD provides approximately 0.16 L (160 mL) of FEV1 AUC. 0-4h (For example, 12 weeks after application).

[0095] In some embodiments, administration of the drug composition (e.g., containing enstatin) to a subject with severe or profound COPD provides at least 0.07 L (70 mL) of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with severe or profound COPD provides at least 0.08 L (e.g., 0.09 L, 0.1 L) of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with severe or profound COPD provides up to 0.14 L (140 mL) of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with severe or profound COPD provides up to 0.13 L (e.g., 0.12 L, 0.11 L, 0.1 L) of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with severe or profound COPD provides approximately 0.07 L to approximately 0.14 L of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with severe or profound COPD provides approximately 0.08 L to approximately 0.12 L of FEV1 AUC. 0-4h (For example, after 12 weeks of administration). In some embodiments, administration of the pharmaceutical composition (e.g., containing enstatin) to a subject with severe or profound COPD provides approximately 0.1 L (e.g., 100 mL) of FEV1 AUC. 0-4h (For example, 12 weeks after application).

[0096] In some implementations, the FEV1AUC of subjects with mild or moderate COPD 0-4h The FEV1 AUC was at least 40% higher than that of subjects with severe or very severe COPD. In some implementations, the FEV1 AUC was higher in subjects with mild or moderate COPD. 0-4h Up to 70% higher than in subjects with severe or very severe COPD. In some implementations, the FEV1 AUC in subjects with mild or moderate COPD is... 0-4h The FEV1 AUC was approximately 50% to 70% higher than in subjects with severe or very severe COPD. In some implementations, the FEV1 AUC was higher in subjects with mild or moderate COPD. 0-4hThe rate was approximately 60% higher than in subjects with severe or very severe COPD.

[0097] In some implementations, the FEV1AUC of subjects with severe or very severe COPD is... 0-4h The FEV1 AUC was at least 40% higher than that of subjects with mild or moderate COPD. In some implementations, the FEV1 AUC was higher in subjects with severe or very severe COPD. 0-4h Up to 70% higher than in subjects with mild or moderate COPD. In some implementations, the FEV1 AUC in subjects with severe or very severe COPD is... 0-4h The FEV1 AUC was approximately 50% to 70% higher than in subjects with mild or moderate COPD. In some implementations, the FEV1 AUC was higher in subjects with severe or very severe COPD. 0-4h It was about 60% higher than in subjects with mild or moderate COPD.

[0098] As described herein, FEV1 can be measured using a spirometry test, which should be understood by a technician as a fully standardized, easily performed, and consistently reproducible measurement of lung function.

[0099] Kidney damage In some embodiments, this document provides methods for treating COPD in subjects with varying levels of renal impairment. In some embodiments, this document provides methods for treating COPD in subjects with moderate renal impairment. Renal impairment in a subject can affect the clearance of enstatin, resulting in altered PK parameters compared to healthy subjects. In some embodiments, the method includes administering (e.g., a therapeutically effective amount) enstatin to the subject. In some embodiments, the method includes administering the pharmaceutical composition provided herein to the subject.

[0100] As described in this article, renal impairment in subjects was determined based on the subject's absolute glomerular filtration rate (aEGFR). For example, individuals with normal to mild renal impairment exhibited an aEGFR greater than or equal to 60 mL / min. Individuals with moderate renal impairment exhibited an aEGFR less than or equal to 60 mL / min. Individuals with normal renal function may exhibit an aEGFR greater than or equal to 90 mL / min.

[0101] In some implementations, subjects with moderate renal impairment exhibit altered PK parameters compared to healthy subjects or those with mild renal impairment. In some implementations, the altered PK parameters include mean C... max T max or AUC 0-tau One or more of them.

[0102] In some embodiments, administration of the pharmaceutical composition provided herein (e.g., containing encefentin) provided different plasma concentrations of encefentin (e.g., as described in Example 1) in subjects with moderate renal impairment compared to healthy subjects or those with mild renal impairment. In some embodiments, the pharmaceutical composition provided herein (e.g., containing encefentin) provided plasma concentrations of encefentin in subjects with moderate renal impairment, comprising an average Cg of about 500 pg / mL to about 700 pg / mL. max In some implementations, the average C in subjects with moderate renal impairment was [missing information]. max The concentration was approximately 550 pg / mL to approximately 650 pg / mL. In some embodiments, the average C in subjects with moderate renal impairment was [missing information]. max It was approximately 604 pg / mL. In some implementations, the average C in subjects with moderate renal impairment was [missing information]. max The concentration is at least 400 pg / mL (e.g., at least 450 pg / mL, at least 500 pg / mL, at least 550 pg / mL, or at least 600 pg / mL). In some embodiments, the average C in subjects with moderate renal impairment is [missing information]. max The concentration was at least 550 pg / mL. In some implementations, the average C in subjects with moderate renal impairment was [missing information]. max The concentration is at most 750 pg / mL (e.g., at most 700 pg / mL, at most 650 pg / mL). In some embodiments, the average C in subjects with moderate renal impairment is [missing information]. max The maximum concentration is 650 pg / mL.

[0103] In some embodiments, the pharmaceutical compositions provided herein (e.g., containing encefentin) provide plasma concentrations of encefentin in healthy subjects or those with mild renal impairment, comprising an average Cg of about 173 mL / min to about 1330 mL / min. max In some embodiments, the pharmaceutical compositions provided herein (e.g., containing encefentin) provide plasma concentrations of encefentin in healthy subjects or those with mild renal impairment, comprising an average Cg of about 150 mL / min to about 1400 mL / min. max In some embodiments, the pharmaceutical compositions provided herein (e.g., containing encefentin) provide plasma concentrations of encefentin in healthy subjects or those with mild renal impairment, comprising an average Cg of about 400 mL / min to about 700 mL / min. maxIn some embodiments, the pharmaceutical compositions provided herein (e.g., containing enstatin) provide plasma concentrations of enstatin in healthy subjects or those with mild renal impairment, comprising at least 100 mL / min of average C60. max In some embodiments, the pharmaceutical compositions provided herein (e.g., containing encefentin) provide plasma concentrations of encefentin in healthy subjects or those with mild renal impairment, comprising an average C0.05 of at least 200 mL / min (e.g., 300 mL / min, 400 mL / min, or 500 mL / min). max In some embodiments, the pharmaceutical compositions provided herein (e.g., containing encefentin) provide plasma concentrations of encefentin in healthy subjects or those with mild renal impairment, comprising an average C0.05 of up to 1000 mL / min. max In some embodiments, the pharmaceutical compositions provided herein (e.g., containing encefentin) provide plasma concentrations of encefentin in healthy subjects or those with mild renal impairment, comprising an average C0.05 of up to 900 mL / min (e.g., 800 mL / min, 700 mL / min, 600 mL / min, or 500 mL / min). max In some embodiments, the pharmaceutical compositions provided herein (e.g., containing encefentin) provide plasma concentrations of encefentin in healthy subjects or those with mild renal impairment, comprising an average C0.05 of approximately 500 mL / min. max In some embodiments, the pharmaceutical compositions provided herein (e.g., containing enstatin) provide plasma concentrations of enstatin in healthy subjects or those with mild renal impairment, comprising an average C0.05 of approximately 522 mL / min. max .

[0104] In some embodiments, administration of the drug composition to subjects with moderate renal impairment provides plasma concentrations containing higher than the average Cg of individuals with normal to mild renal impairment. max In some implementations, the average C max C compared to subjects without moderate renal impairment who received the drug composition max At least 10% higher. In some embodiments, the C-value is higher in subjects who do not have moderate renal impairment after receiving the drug composition. max In comparison, the average C max The proportion of subjects with moderate renal impairment is at least 5% (e.g., at least 6%, at least 7%, at least 8%, or at least 9%). In some embodiments, the C-value is higher than that of subjects without moderate renal impairment who are given the drug composition. max In comparison, the average C maxIn subjects with moderate renal impairment, the proportion is up to 15% (e.g., up to 14%, up to 13%, up to 12%, up to 11%). In some embodiments, the C-value is higher in subjects who do not have moderate renal impairment and are given the drug composition. max In comparison, the average C max The rate was approximately 16% higher in subjects with moderate renal impairment. In some cases, the C-value was higher in subjects with moderate renal impairment and those with normal to mild renal impairment. max Showing Figure 1B middle.

[0105] In some embodiments, administration of the drug composition to subjects with normal to mild renal impairment provides plasma concentrations containing higher than the average Cg of individuals with moderate renal impairment. max In some implementations, the average C max C compared to subjects with normal renal function to mild renal impairment who received the drug composition max At least 10% higher. In some embodiments, the C-value is higher in subjects who have no normal renal function to have mild renal impairment after receiving the drug composition. max In comparison, the average C max The percentage of subjects with normal to mild renal impairment is at least 5% (e.g., at least 6%, at least 7%, at least 8%, or at least 9%). In some embodiments, the C-value is higher in subjects who do not have normal to mild renal impairment and are given the drug composition. max In comparison, the average C max Up to 15% of subjects with normal to mild renal impairment (e.g., up to 14%, up to 13%, up to 12%, or up to 11%).

[0106] In some embodiments, administration of the pharmaceutical composition provided herein (e.g., containing encefentin) provides plasma concentrations of encefentin in subjects with moderate renal impairment, comprising a mean AUC of approximately 2600 pg / mL*h to approximately 3600 pg / mL*h. 0-tau (Exposure). In some embodiments, the pharmaceutical compositions provided herein provide plasma concentrations of enstatin comprising an average AUC of about 3000 pg / mL*h to about 3400 pg / mL*h. 0-tau (Exposure). In some embodiments, the pharmaceutical compositions provided herein provide plasma concentrations of enstatin in subjects with moderate renal impairment, comprising a mean AUC of at least 2500 pg / mL*h (e.g., at least 2600 pg / mL*h, at least 2800 pg / mL*h, at least 3000 pg / mL*h, or at least 3100 pg / mL*h). 0-tau(Exposure). In some embodiments, the pharmaceutical compositions provided herein deliver plasma concentrations of enstatin in subjects with moderate renal impairment, comprising a mean AUC of approximately 3200 pg / mL*h. 0-tau (Exposure). In some embodiments, the pharmaceutical compositions provided herein provide plasma concentrations of enstatin in subjects with moderate renal impairment, comprising a mean AUC of up to 3750 pg / mL*h (e.g., up to 3700 pg / mL*h, up to 3600 pg / mL*h, up to 3500 pg / mL*h, up to 3400 pg / mL*h, or up to 3300 pg / mL*h). 0-tau (Exposure).

[0107] In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin in healthy subjects or subjects with mild renal impairment, comprising a mean AUC of approximately 882 pg / mL*h to approximately 7500 pg / mL*h. 0-tau (Exposure). In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin in healthy subjects or subjects with mild renal impairment, comprising a mean AUC of approximately 800 pg / mL*h to approximately 7500 pg / mL*h. 0-tau (Exposure). In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin in healthy subjects or subjects with mild renal impairment, comprising a mean AUC of at least 800 pg / mL*h. 0-tau (Exposure). In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin in healthy subjects or subjects with mild renal impairment, comprising a mean AUC of at least 900 pg / mL*h (e.g., 1200 pg / mL*h, 1400 pg / mL*h, 1600 pg / mL*h, 2000 pg / mL*h, 2200 pg / mL*h, or 2400 pg / mL*h). 0-tau (Exposure). In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin in healthy subjects or subjects with mild renal impairment, comprising a mean AUC of up to 8000 pg / mL*h. 0-tau (Exposure). In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin in healthy subjects or subjects with mild renal impairment, comprising a mean AUC of up to 8000 pg / mL*h. 0-tau(Exposure). In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin in healthy subjects or subjects with mild renal impairment, comprising a mean AUC of up to 7000 pg / mL*h (e.g., 6000 pg / mL*h, 5000 pg / mL*h, 4000 pg / mL*h, 3000 pg / mL*h, or 2500 pg / mL*h). 0-tau (Exposure). In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin in healthy subjects or subjects with mild renal impairment, comprising a mean AUC of approximately 2500 pg / mL*h. 0-tau (Exposure). In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin in healthy subjects or subjects with mild renal impairment, comprising a mean AUC of 2450 pg / mL*h. 0-tau (Exposure).

[0108] In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin, which contain the mean AUC in subjects with moderate renal impairment. 0-tau (Exposure) AUC compared to individuals without moderate renal impairment (e.g., those with normal renal function or mild renal impairment). 0-tau Different. In some embodiments, the pharmaceutical compositions provided herein provide plasma concentrations of enstatin containing a mean AUC 0-tau The exposure was at least 25% higher in subjects with moderate renal impairment than in subjects without moderate renal impairment (e.g., normal renal function or mild renal impairment). In some embodiments, the pharmaceutical compositions provided herein provide plasma concentrations of enstatin containing a mean AUC 0-tau The exposure was at least 10% higher in subjects with moderate renal impairment than in subjects without moderate renal impairment (e.g., normal renal function or mild renal impairment) (e.g., 12%, 14%, 16%, 18%, or 20% higher). In some embodiments, the pharmaceutical compositions provided herein provide plasma concentrations of enstatin containing a mean AUC 0-tau The (exposure) was up to 35% higher in subjects with moderate renal impairment than in subjects without moderate renal impairment (e.g., normal renal function or mild renal impairment) (e.g., 30%, 28%, 27%, or 26% higher). In some cases, the AUC was higher in individuals with moderate renal impairment than in individuals with normal to mild renal function. 0-tau Showing Figure 1A middle.

[0109] In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin, comprising the mean AUC in subjects with normal renal function to mild renal impairment. 0-tau (Exposure) and AUC in individuals with normal to mild renal impairment (e.g., normal or mild renal impairment). 0-tau Different. In some embodiments, the pharmaceutical compositions provided herein provide plasma concentrations of enstatin containing a mean AUC 0-tau The (exposure) was at least 25% higher in subjects with normal to mild renal function than in subjects without normal to mild renal function (e.g., normal or mild renal function). In some embodiments, the pharmaceutical compositions provided herein provide plasma concentrations of enstatin containing a mean AUC 0-tau (Exposure) is at least 10% higher in subjects with normal to mild renal function than in subjects without normal to mild renal function (e.g., normal or mild renal function) (e.g., 12%, 14%, 16%, 18%, or 20% higher). In some embodiments, the pharmaceutical compositions provided herein provide plasma concentrations of enstatin containing a mean AUC 0-tau (Exposure) was up to 35% higher in subjects with normal to mild renal function than in subjects with no to mild renal function (e.g., 30%, 28%, 27%, or 26% higher).

[0110] In some embodiments, administration of the pharmaceutical composition provided herein provides plasma concentrations of enstatin, which contain a mean T in subjects with moderate renal impairment. max Unlike subjects without moderate renal impairment (e.g., those with normal kidney function or mild renal impairment), the pharmaceutical compositions provided herein deliver plasma concentrations of enstatin, which, in subjects with moderate renal impairment, contain a mean T... max The results are substantially identical to those in subjects without moderate renal impairment (e.g., those with normal renal function or mild renal impairment). In some embodiments, the pharmaceutical compositions provided herein deliver plasma concentrations of enstatin that contain a mean T0.05 of approximately 1 hour to approximately 2 hours in subjects with moderate renal impairment. max In some embodiments, the pharmaceutical compositions provided herein deliver plasma concentrations of enstatin that contain a mean T1 of approximately 1.2 hours to approximately 1.7 hours in subjects with moderate renal impairment. maxIn some embodiments, the pharmaceutical compositions provided herein deliver plasma concentrations of enstatin containing at least 0.8 hours (e.g., at least 0.9 hours, at least 1 hour, at least 1.2 hours, at least 1.4 hours) of mean T in subjects with moderate renal impairment. max In some embodiments, the pharmaceutical compositions provided herein deliver plasma concentrations of encefentin that contain a mean T0.05 for up to 2.2 hours (e.g., up to 2 hours, up to 1.8 hours, up to 1.7 hours, up to 1.6 hours) in subjects with moderate renal impairment. max In some implementations, the average T1 of individuals with moderate renal impairment and individuals without moderate renal impairment (e.g., normal renal function or mild renal impairment) is... max Showing Figure 2 middle.

[0111] The pharmacokinetic parameters of plasma concentrations provided herein can be measured at any suitable interval after administration of the pharmaceutical composition. In some embodiments, the average Cp max Average AUC 0-tau and average T max Measurements are taken at intervals, wherein the intervals comprise two or more of the following: 1.0 hour (±0.5 hours), 1.5 hours (±0.5 hours), 2.5 hours (±0.5 hours), 3.0 hours (±0.5 hours), 4.0 hours (±1 hour), 6.0 hours (±1 hour), 8.0 hours (±1 hour), 10.0 hours (±1 hour), 12.0 hours (±1 hour), 24.0 hours (±1 hour), 36.0 hours (±1 hour), 48.0 hours (±1 hour), 56.0 hours (±1 hour), and 60.0 hours (±1 hour). In some embodiments, the average C max Measurements are performed at intervals, wherein the intervals comprise two or more of the following: 1.0 hour (±0.5 hours), 1.5 hours (±0.5 hours), 2.5 hours (±0.5 hours), 3.0 hours (±0.5 hours), 4.0 hours (±1 hour), 6.0 hours (±1 hour), 8.0 hours (±1 hour), 10.0 hours (±1 hour), 12.0 hours (±1 hour), 24.0 hours (±1 hour), 36.0 hours (±1 hour), 48.0 hours (±1 hour), 56.0 hours (±1 hour), and 60.0 hours (±1 hour). In some embodiments, the average AUC is... 0-tauMeasurements are taken at intervals, wherein the intervals comprise two or more of the following: 1.0 hour (±0.5 hours), 1.5 hours (±0.5 hours), 2.5 hours (±0.5 hours), 3.0 hours (±0.5 hours), 4.0 hours (±1 hour), 6.0 hours (±1 hour), 8.0 hours (±1 hour), 10.0 hours (±1 hour), 12.0 hours (±1 hour), 24.0 hours (±1 hour), 36.0 hours (±1 hour), 48.0 hours (±1 hour), 56.0 hours (±1 hour), and 60.0 hours (±1 hour). In some embodiments, the average T... max Measurements are taken at intervals, wherein the intervals comprise two or more of the following: 1.0 hour (±0.5 hours), 1.5 hours (±0.5 hours), 2.5 hours (±0.5 hours), 3.0 hours (±0.5 hours), 4.0 hours (±1 hour), 6.0 hours (±1 hour), 8.0 hours (±1 hour), 10.0 hours (±1 hour), 12.0 hours (±1 hour), 24.0 hours (±1 hour), 36.0 hours (±1 hour), 48.0 hours (±1 hour), 56.0 hours (±1 hour), and 60.0 hours (±1 hour).

[0112] Liver damage In some embodiments, this document provides methods for treating COPD in subjects with varying liver function. In some embodiments, the subject's liver function includes healthy liver function, moderate liver impairment, or severe liver impairment. In some embodiments, this document provides methods for treating COPD in subjects with liver function including healthy liver function. In some embodiments, this document provides methods for treating COPD in subjects with liver function including moderate liver impairment. In some embodiments, this document provides methods for treating COPD in subjects with liver function including severe liver impairment.

[0113] In some cases, liver function in subjects is determined using the Child-Pugh score. The Child-Pugh score categorizes liver function (e.g., severity of liver disease) based on the degree of ascites, serum bilirubin and albumin concentrations, prothrombin time, and encephalopathy. A Child-Pugh score of 5–6 is considered Grade A (well-compensated disease). A Child-Pugh score of 7–9 is considered Grade B (significantly impaired function). A Child-Pugh score of 10–15 is considered Grade C (decompensated disease). Technicians should understand that the Child-Pugh score is the accepted method for defining liver function in subjects. Using the Child-Pugh score, subjects are categorized into groups including: healthy liver function, moderate liver impairment, or severe liver impairment. Subjects classified as Grade A according to the Child-Pugh score can be individuals with normal liver function as used herein. Subjects classified as Grade B according to the Child-Pugh score can be individuals with moderate liver impairment as used herein. Subjects classified as Grade C according to the Child-Pugh score can be individuals with severe liver damage, as used in this article.

[0114] In some embodiments, the pharmaceutical compositions provided herein provide an AUC t,ss The plasma concentration of enstatin (area under the steady-state curve). In some cases, regardless of the subject's liver function, the AUC... t,ss Essentially the same. In some cases, this indicates that (1) patients with moderate or severe liver damage can respond to encefentin as a treatment for COPD, and (2) the encefentin compositions described herein are safe for subjects with varying levels of liver damage, ranging from healthy to severely damaged.

[0115] In some embodiments, administration of the pharmaceutical composition provides an AUC t,ss The plasma concentration, for example, in Example 1 and Figure 3 As described above. In some implementations, AUC t,ss The AUC is approximately 5000 pg / mL*h to approximately 10000 pg / mL*h. In some embodiments, the AUC... t,ss The AUC is approximately 5000 pg / mL*h to approximately 7500 pg / mL*h. In some embodiments, the AUC... t,ss The AUC is at least 4000 pg / mL*h (e.g., at least 4200 pg / mL*h, at least 4500 pg / mL*h, at least 4700 pg / mL*h, at least 4900 pg / mL*h, or at least 5000 pg / mL*h). In some embodiments, the AUC... t,ssThe maximum is 10,000 pg / mL*h (e.g., up to 9,500 pg / mL*h, up to 9,000 pg / mL*h, up to 8,500 pg / mL*h, up to 8,000 pg / mL*h, or up to 7,500 pg / mL*h). In some embodiments, the AUC of healthy subjects... t,ss AUC compared with subjects with moderate liver damage t,ss Essentially, there is no difference. In some implementations, the AUC of healthy subjects... t,ss AUC compared with subjects with severe liver damage t,ss Essentially, there is no difference. In some implementations, the AUC of subjects with moderate liver damage is... t,ss AUC compared with subjects with severe liver damage t,ss Basically, there is no difference.

[0116] In some implementations, administration of the pharmaceutical composition provides healthy subjects with an AUC. t,ss The plasma concentration, for example, in Example 1 and Figure 3 As described above. In some implementations, the AUC of healthy subjects... t,ss The AUC is approximately 5000 pg / mL*h to approximately 10000 pg / mL*h. In some implementations, the AUC of healthy subjects... t,ss The AUC is approximately 5000 pg / mL*h to approximately 7500 pg / mL*h. In some implementations, the AUC of healthy subjects... t,ss The AUC of at least 4000 pg / mL*h (e.g., at least 4200 pg / mL*h, at least 4500 pg / mL*h, at least 4700 pg / mL*h, at least 4900 pg / mL*h, or at least 5000 pg / mL*h). In some embodiments, the AUC of healthy subjects... t,ss The maximum is 10,000 pg / mL*h (e.g., up to 9,500 pg / mL*h, up to 9,000 pg / mL*h, up to 8,500 pg / mL*h, up to 8,000 pg / mL*h, or up to 7,500 pg / mL*h). In some embodiments, the AUC of healthy subjects... t,ss It is approximately 7000 pg / mL*h.

[0117] In some embodiments, administration of the pharmaceutical composition provides subjects with moderate hepatic impairment with an AUC of [missing information]. t,ss The plasma concentration, for example, in Example 1 and Figure 3 As described in [the document]. In some implementations, the AUC of subjects with moderate liver damage [is used]. t,ssThe AUC was approximately 4500 pg / mL*h to approximately 11000 pg / mL*h. In some embodiments, the AUC of subjects with moderate hepatic impairment was... t,ss The AUC is at least 4000 pg / mL*h (e.g., at least 4200 pg / mL*h, at least 4500 pg / mL*h, at least 4700 pg / mL*h, at least 4900 pg / mL*h, or at least 5000 pg / mL*h). In some embodiments, the AUC of subjects with moderate hepatic impairment is... t,ss The maximum is 12,000 pg / mL*h (e.g., up to 11,000 pg / mL*h, up to 9,500 pg / mL*h, up to 9,000 pg / mL*h, up to 8,500 pg / mL*h, up to 8,000 pg / mL*h, or up to 7,500 pg / mL*h). In some embodiments, the AUC of subjects with moderate hepatic impairment is... t,ss The AUC is approximately 6000 pg / mL*h. In some implementations, the AUC is [not specified] for subjects with moderate hepatic impairment. t,ss It is approximately 5500 pg / mL*h.

[0118] In some embodiments, administration of the pharmaceutical composition provides subjects with severe hepatic impairment with an AUC of [missing information]. t,ss The plasma concentration, for example, in Example 1 and Figure 3 As described in [the document]. In some implementations, the AUC of subjects with severe liver damage [is used]. t,ss The AUC is approximately 5000 pg / mL*h to approximately 7500 pg / mL*h. In some implementations, the AUC is [not specified] for subjects with severe hepatic impairment. t,ss The AUC is approximately 5500 pg / mL*h to approximately 7000 pg / mL*h. In some embodiments, the AUC is [not specified] for subjects with severe hepatic impairment. t,ss The AUC is at least 5000 pg / mL*h (e.g., at least 5200 pg / mL*h, at least 5500 pg / mL*h, at least 5700 pg / mL*h, at least 5900 pg / mL*h, or at least 6000 pg / mL*h). In some embodiments, the AUC of subjects with severe hepatic impairment is... t,ss The maximum is 7500 pg / mL*h (e.g., up to 7000 pg / mL*h, up to 6500 pg / mL*h, or up to 6000 pg / mL*h). In some embodiments, the AUC of subjects with severe hepatic impairment is... t,ss The AUC is approximately 6500 pg / mL*h. In some implementations, the AUC is [not specified] for subjects with severe hepatic impairment. t,ss It is approximately 7000 pg / mL*h.

[0119] Valley value lung function In some embodiments, this document provides a method for increasing trough lung function in subjects with COPD, the method comprising administering to the subject (e.g., a therapeutically effective amount) enstatin. In some embodiments, this document provides a method for increasing trough lung function in subjects with COPD, the method comprising administering to the subject a pharmaceutical composition (e.g., containing enstatin) as described in other parts of this document.

[0120] In some cases, improving trough lung function includes improving morning and nighttime trough lung function. In some implementations, improving trough lung function includes improving morning trough lung function. In some implementations, it includes improving nighttime trough lung function.

[0121] In some embodiments, this document provides methods for increasing trough lung function in subjects with COPD, wherein the subjects have healthy liver function, moderate liver impairment, or severe liver impairment. In some embodiments, this document provides methods for increasing trough lung function in subjects with COPD, wherein the subjects have healthy liver function. In some embodiments, this document provides methods for increasing trough lung function in subjects with COPD, wherein the subjects have moderate liver impairment. In some embodiments, this document provides methods for increasing trough lung function in subjects with COPD, wherein the subjects have severe liver impairment. In some embodiments, the subject's liver function is determined using the Child-Pugh score as described above.

[0122] In some embodiments, this document provides methods for increasing trough lung function in subjects with COPD, wherein the subjects have healthy kidney function or mild kidney impairment. In some embodiments, this document provides methods for increasing trough lung function in subjects with COPD, wherein the subjects have moderate kidney impairment.

[0123] In some embodiments, this document provides a method for treating COPD in a subject, comprising administering (e.g., a therapeutically effective amount) ensifine, wherein the subject is susceptible to sleep disturbances. In some embodiments, this document provides a method for treating COPD in a subject, comprising administering a pharmaceutical composition described in other parts of this document, wherein the subject is susceptible to sleep disturbances.

[0124] In some cases, an increase in trough-level lung function in a subject is determined by measuring an increase in trough-level FEV1 (e.g., the subject's FEV1 shortly before administration of a compound that is part of maintenance therapy). Improvements in trough-level lung function can, for example, result from changes in maintenance therapy medications.

[0125] In some embodiments, the method described herein includes increasing morning trough lung function (e.g., trough lung function after sleep). Morning trough lung function can be measured by determining the subject's FEV1 shortly before morning administration of the compound as part of maintenance therapy. In some embodiments, FEV1 can be measured less than one hour before morning administration of encefentanil. Morning trough FEV1 can be FEV1 measured between 11.5 and 12 hours after the previous night's dose.

[0126] In some implementations, improvements in trough lung function can improve sleep in COPD subjects. In some cases, this can be important in subjects susceptible to sleep disturbances. Subjects susceptible to sleep disturbances often have conditions that directly affect their ability to fall asleep (e.g., insomnia or sleep apnea) or conditions that indirectly make it more difficult for them to fall asleep (e.g., skin conditions that irritate the skin and make it more difficult for patients to fall asleep or stay asleep, such as psoriasis).

[0127] As used herein, “patients susceptible to sleep disturbances” generally refers to patients suffering from one or more of the following conditions or disorders: obesity, insomnia, sleep apnea, narcolepsy, restless legs syndrome, REM sleep behavior disorder, circadian rhythm sleep disorder, parasomnia, depression, anxiety, psoriasis, dermatitis, eczema, or urticaria. In some embodiments, encefentin or a pharmaceutical composition containing encefentin may be used to treat COPD in subjects with both COPD and sleep apnea. In some embodiments, encefentin or a pharmaceutical composition containing encefentin may be used to treat COPD in subjects with both COPD and skin conditions such as psoriasis, dermatitis, eczema, or urticaria.

[0128] In some implementations, improvements in trough lung function can significantly help COPD patients with exercise. In some cases, the patient is obese.

[0129] acute exacerbation of COPD In some embodiments, this document provides a method for treating the frequency and / or severity of COPD exacerbations in subjects with COPD, the method comprising administering to the subject enstatin (e.g., a therapeutically effective amount) contained in a pharmaceutical composition provided herein. In some embodiments, this document provides a method for treating the frequency of COPD exacerbations in subjects, the method comprising administering to the subject enstatin (e.g., a therapeutically effective amount) contained in a pharmaceutical composition provided herein. In some embodiments, this document provides a method for treating the severity of COPD exacerbations in subjects, the method comprising administering to the subject enstatin (e.g., a therapeutically effective amount) contained in a pharmaceutical composition provided herein. In some embodiments, this document also provides a method for increasing the time to the first COPD exacerbation in subjects with COPD, which comprises administering enstatin (e.g., a therapeutically effective amount) contained in a pharmaceutical composition provided herein.

[0130] COPD exacerbations can be life-threatening and are associated with comorbidities. They can also be associated with an irreversible increase in airflow obstruction, which can lead to higher hospitalization frequency and an increased risk of death. Exacerbations are also important events in the progression of COPD in patients because they negatively impact health-related quality of life and can be associated with a accelerated decline in lung function and increased mortality. Therefore, approaches to treating / reducing the frequency of COPD exacerbations are desirable.

[0131] In some embodiments, this document provides a method for treating COPD in a subject, comprising administering to the subject (e.g., a therapeutically effective amount) enstatin or a pharmaceutically acceptable salt thereof, wherein the subject is susceptible to acute exacerbations of COPD. In some embodiments, this document provides a method for treating COPD in a subject, comprising administering to the subject a pharmaceutical composition provided in other parts of this document, wherein the subject is susceptible to acute exacerbations of COPD.

[0132] In some embodiments, this document provides a method for treating COPD in a subject, comprising administering to the subject a pharmaceutical composition (e.g., containing enstatin) as described elsewhere in this document, wherein the subject is susceptible to acute exacerbations of COPD and has normal liver function, moderate hepatic impairment, or severe hepatic impairment. In some embodiments, this document provides a method for treating COPD in a subject, comprising administering to the subject a pharmaceutical composition (e.g., containing enstatin) as described elsewhere in this document, wherein the subject is susceptible to acute exacerbations of COPD and has normal liver function. In some embodiments, this document provides a method for treating COPD in a subject, comprising administering to the subject a pharmaceutical composition (e.g., containing enstatin) as described elsewhere in this document, wherein the subject is susceptible to acute exacerbations of COPD and has moderate hepatic impairment. In some embodiments, this document provides a method for treating COPD in a subject, comprising administering to the subject a pharmaceutical composition (e.g., containing enstatin) as described elsewhere in this document, wherein the subject is susceptible to acute exacerbations of COPD and has severe hepatic impairment. In some embodiments, the subject's liver function is determined using a Child-Pugh score as described elsewhere in this document.

[0133] In some embodiments, this document provides a method for treating COPD in a subject, comprising administering to the subject a pharmaceutical composition (e.g., containing enstatin) as described elsewhere in this document, wherein the subject is susceptible to acute exacerbations of COPD and has normal to mild or moderate renal impairment.

[0134] In some embodiments, encefentin or a pharmaceutically acceptable salt thereof can reduce the frequency and / or severity of COPD exacerbations in subjects with COPD. For example, while being treated (e.g., as maintenance therapy) with the pharmaceutical composition provided herein (e.g., containing encefentin), a subject may experience two or fewer (e.g., one or zero) COPD exacerbations per year. The number of COPD exacerbations experienced by a subject per year during treatment with the pharmaceutical composition provided herein (e.g., containing encefentin) may be one to three fewer than the number of COPD exacerbations experienced by the subject per year prior to treatment with encefentin.

[0135] In some embodiments, administration of the pharmaceutical composition provided herein reduces the rate of acute exacerbations of COPD by about 30% to about 50%. In some embodiments, administration of the pharmaceutical composition provided herein reduces the rate of acute exacerbations of COPD by about 35% to about 45%. In some embodiments, administration of the pharmaceutical composition provided herein reduces the rate of acute exacerbations of COPD by at least 25%. In some embodiments, administration of the pharmaceutical composition provided herein reduces the rate of acute exacerbations of COPD by at least 30% (e.g., 32%, 34%, 36%, 38%, 40%, or 42%). In some embodiments, administration of the pharmaceutical composition provided herein reduces the rate of acute exacerbations of COPD by up to 50% (e.g., 48%, 46%, 44%, 42%, or 40%). In some embodiments, administration of the pharmaceutical composition provided herein reduces the rate of acute exacerbations of COPD by about 36%, 43%, or 44%. In some embodiments, administration of the pharmaceutical composition provided herein reduces the rate of acute exacerbations of COPD by about 40%. In some embodiments, administration of the pharmaceutical compositions provided herein reduced the rate of acute exacerbations of COPD by approximately 36%. This reduction in acute exacerbations of COPD can occur in any subject subgroup, including subjects with varying degrees of kidney or liver impairment, as described in other parts of this document.

[0136] In some embodiments, administration of the pharmaceutical composition provided herein may provide a longer time to the first moderate or severe COPD exacerbation (e.g., compared to subjects administered placebo). In some embodiments, administration of the pharmaceutical composition provided herein may provide a reduction of at least 25% in the risk of COPD exacerbation (e.g., over 24 weeks of treatment). In some embodiments, administration of the pharmaceutical composition provided herein may provide a reduction of at least 30% (e.g., 32%, 34%, 36%, or 38%) in the risk of COPD exacerbation. In some embodiments, administration of the pharmaceutical composition provided herein may provide a reduction of up to 60% in the risk of COPD (e.g., 58%, 56%, 52%, 50%, 46%, or 42%). In some embodiments, administration of the pharmaceutical composition provided herein may provide a reduction of approximately 38% in the risk of COPD exacerbation. In some embodiments, administration of the pharmaceutical composition provided herein may provide a reduction of approximately 52% in the risk of COPD exacerbation (e.g., over 48 weeks of treatment). In some cases, a reduction in the risk of acute exacerbations of COPD can be determined by the Cox proportional hazards test and / or log-rank test.

[0137] In some implementations, enstatin or a pharmaceutically acceptable salt thereof may increase the time to first COPD exacerbation in a subject. In some cases, a subject may not have yet experienced a COPD exacerbation, and enstatin may increase the time until the subject experiences its first COPD exacerbation (e.g., the first COPD exacerbation is delayed). Therefore, enstatin or a pharmaceutically acceptable salt thereof may reduce the risk of COPD exacerbation in subjects with COPD.

[0138] As described in this article, an acute exacerbation of COPD may include one or more of the following: shortness of breath, increased cough, increased sputum volume, purulent sputum, wheezing, sore throat, flu-like symptoms, and fever. Purulent sputum is a color change from colorless to yellow-green in naturally expectorated samples. An acute exacerbation of COPD may last for at least one day or at least two days. In some cases, an acute exacerbation of COPD lasts for one day. In some cases, an acute exacerbation of COPD lasts for at least one day. In some cases, an acute exacerbation of COPD lasts for at least two days.

[0139] In some embodiments, the method of treating the frequency and / or severity of COPD exacerbations also treats dyspnea in the subject. In some embodiments, the method of treating the frequency and / or severity of COPD exacerbations also reduces the frequency of cough in the subject. In some embodiments, the method of treating the frequency and / or severity of COPD exacerbations also reduces sputum volume in the subject. In some embodiments, the method of treating the frequency and / or severity of COPD exacerbations also improves purulent sputum in the subject. In some embodiments, the method of treating the frequency and / or severity of COPD exacerbations also improves wheezing in the subject. In some embodiments, the method of treating the frequency and / or severity of COPD exacerbations also improves sore throat in the subject. In some embodiments, the method of treating the frequency and / or severity of COPD exacerbations also improves cold symptoms in the subject. In some embodiments, the method of treating the frequency and / or severity of COPD exacerbations also improves fever in the subject.

[0140] In some implementations, an acute exacerbation of COPD includes a worsening of two or more of the following primary symptoms for at least two consecutive days: dyspnea, sputum volume, and purulent sputum. In some implementations, an acute exacerbation of COPD includes any primary symptom along with any of the following secondary symptoms for at least two consecutive days: sore throat, cold (runny nose and / or nasal congestion), fever without other cause (oral temperature >37.5 °C), and increased cough. In some cases, an acute exacerbation of COPD includes a worsening of two or more of the primary symptoms (dyspnea, sputum volume, and purulent sputum) for at least two consecutive days.

[0141] COPD exacerbations can be moderate or severe. A moderate exacerbation is defined as a worsening of COPD symptoms requiring at least three days of treatment with oral / systemic corticosteroids and / or antibiotics (as defined above). A severe exacerbation is defined as a worsening of COPD symptoms requiring hospitalization (as defined above). In some embodiments, enstatin or a pharmaceutically acceptable salt thereof reduces the severity of COPD exacerbations in patients and can be used to prevent severe COPD exacerbations in subjects. In some embodiments, enstatin or a pharmaceutically acceptable salt thereof reduces the severity of COPD exacerbations. In some embodiments, enstatin or a pharmaceutically acceptable salt thereof reduces the severity of COPD exacerbations. In some cases, subjects may not experience a severe COPD exacerbation within one year after the first administration of the compound.

[0142] In some embodiments, the pharmaceutical compositions provided herein extend the time to an acute exacerbation of COPD. In some embodiments, the pharmaceutical compositions provided herein may extend the time to an acute exacerbation of COPD by at least one week. In some embodiments, the pharmaceutical compositions provided herein may extend the time to an acute exacerbation of COPD by at least two weeks. In some embodiments, the pharmaceutical compositions provided herein may extend the time to an acute exacerbation of COPD by at least one month. In some embodiments, the pharmaceutical compositions provided herein may extend the time to an acute exacerbation of COPD by at least two months. In some embodiments, the pharmaceutical compositions provided herein may extend the time to an acute exacerbation of COPD by at least three, four, five, or six months.

[0143] As described herein, “subjects susceptible to acute exacerbations of COPD” can be subjects with one or more comorbidities (other than COPD). In some cases, the subject may have one or more diseases or conditions selected from: asthma, pulmonary hypertension, bronchiectasis, allergy, lung cancer, chest infection, cystic fibrosis, pulmonary fibrosis, pneumonia, hay fever, allergic rhinitis, bronchitis, emphysema, adult respiratory distress syndrome (ARDS), interstitial lung disease, or tuberculosis, optionally wherein the asthma is allergic asthma, steroid-resistant asthma, severe asthma, or childhood asthma. Patients susceptible to acute exacerbations of COPD may have a chronic bronchitis etiology, may have impaired lung function (e.g., 30% to 70% of predicted FEV1), or may have COPD symptoms despite treatment with a long-acting muscarinic receptor antagonist (LAMA) or a long-acting beta-adrenergic receptor agonist (LABA).

[0144] In some embodiments, the pharmaceutical compositions provided herein can be used to treat COPD in subjects who have both COPD and asthma. In some embodiments, enstatin or a pharmaceutically acceptable salt thereof can be used to treat subjects who have both COPD and pulmonary hypertension. In some embodiments, the pharmaceutical compositions provided herein can be used to treat subjects who have both COPD and bronchiectasis.

[0145] In some implementation schemes, risk factors for acute exacerbations of COPD include: high serum immunoglobulin (Ig), a history of tuberculosis, severe airflow obstruction, chest infection, and one or more hospitalizations in the past year due to acute exacerbations of COPD.

[0146] In some embodiments, the subject described herein may have experienced one or more acute exacerbations of COPD within one year prior to the first administration of enstatin or a pharmaceutically acceptable salt thereof. In some embodiments, the subject may have experienced two or more acute exacerbations of COPD within one year prior to the first administration of the pharmaceutical composition described herein. In some embodiments, the subject may have experienced at least one severe acute exacerbation of COPD (e.g., requiring hospitalization) within the preceding year. The subject may have experienced one or more acute exacerbations of COPD within six months prior to the first administration of the pharmaceutical composition described herein, or within one month prior to the first administration of the pharmaceutical composition described herein.

[0147] Application method In some embodiments, the method provided herein includes administering a therapeutically effective amount of encefentin to a subject. In some embodiments, the therapeutically effective amount of encefentin comprises a dose of encefentin as described in other parts of this document. In some embodiments, the therapeutically effective amount of encefentin is included in the pharmaceutical composition provided herein.

[0148] In some embodiments, the methods provided herein include administering a pharmaceutical composition to a subject by inhalation. In some embodiments, a pharmaceutical composition comprising enstatin and one or more acceptable excipients or diluents is administered to a subject by inhalation. In some embodiments, administration by inhalation is performed using a nebulizer, a pressure-controlled metered-dose inhaler (pMDI), or a dry powder inhaler (DPI). In some embodiments, administration by inhalation is performed using a nebulizer. In some embodiments, administration by inhalation is performed using a pressure-controlled metered-dose inhaler (pMDI). In some embodiments, administration by inhalation is performed using a dry powder inhaler (DPI).

[0149] In some embodiments, the methods provided herein include administering a pharmaceutical composition via inhalation from a nebulizer. The nebulizer atomizes the liquid pharmaceutical composition into an aerosol, which is inhaled into the patient's respiratory tract. Non-limiting examples of nebulizers include soft fog nebulizers, vibrating mesh 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 TMPulmonaryDelivery System (Aradigm Corp) and Pari LC Plus Reusable Nebuliser (Pari GmbH). Atomizers can be, for example, those with PARI Vios. ® PRO Aerosol Delivery System PARI BOY ® A PARILC Sprint nebulizer with a compressor. Encerfentin can be inhaled via the nebulizer for 1 to 15 minutes. The drug composition can be inhaled via the nebulizer for about 1 to about 15 minutes. In some embodiments, the drug composition can be inhaled for at least 1 minute. In some embodiments, the drug composition can be inhaled for about 1 minute to about 12 minutes, about 1 minute to about 8 minutes, about 1 minute to about 4 minutes, about 3 minutes to about 15 minutes, about 4 minutes to about 10 minutes, or about 6 minutes to about 12 minutes. In some embodiments, the drug composition is inhaled via the nebulizer for about 5 to about 7 minutes. In some embodiments, the drug composition is inhaled via the nebulizer for about 5 minutes. In some embodiments, the drug composition is inhaled via the nebulizer for about 6 minutes. In some embodiments, the drug composition is inhaled via the nebulizer for about 7 minutes.

[0150] Dosing regimen The methods provided herein include administering the pharmaceutical composition to a subject at any frequency necessary to achieve therapeutic efficacy, as determined by a technician. In some embodiments, the subject is provided with a pharmaceutical composition containing encefentin as maintenance therapy. In some embodiments, the methods provided herein include administering the pharmaceutical composition to the subject once, twice, or three times daily, for example, twice or three times daily. In some embodiments, the method includes administering the pharmaceutical composition to the subject once daily. In some embodiments, the methods provided herein include administering the pharmaceutical composition to the subject twice daily (e.g., as maintenance therapy twice daily). In some embodiments, the method includes administering the pharmaceutical composition to the subject three times daily. In some embodiments, the method includes administering encefentin to the subject at least once daily. In some embodiments, the method includes administering a first dose of the pharmaceutical composition in the morning (e.g., within 3 hours of waking up) and a second dose of the pharmaceutical composition in the evening (e.g., within 3 hours before bedtime). In some embodiments, the morning and evening doses are administered approximately 10 to approximately 14 hours apart. In some embodiments, the morning and evening doses are administered approximately 12 hours apart.

[0151] The encefentin described herein can be administered at any suitable therapeutically effective dose. In some embodiments, the daily dose of encefentin is from about 0.1 mg to about 20 mg. In some embodiments, the method described herein comprises administering a total daily dose of encefentin of about 0.5 mg to about 10 mg. In some embodiments, the total daily dose of encefentin (e.g., encefentin free base) is from about 5 mg to about 7 mg. In some embodiments, the total daily dose of encefentin is about 6 mg per day. In some cases, the total daily dose of encefentin may be 6.0 mg.

[0152] The methods described herein may include administering encefentin (e.g., or a pharmaceutical composition containing encefentin) twice daily in two separate doses of the same or similar dosage. In some cases, the method may include administering the compound to a subject twice daily in a first dose of about 1 mg to about 5 mg and a second dose of about 1 mg to about 5 mg. In some embodiments, the method includes administering encefentin (e.g., or a pharmaceutical composition containing encefentin) twice daily in a first dose of about 2 mg to about 4 mg and a second dose of about 2 mg to about 4 mg. In some embodiments, the method includes administering encefentin (e.g., or a pharmaceutical composition containing encefentin) twice daily in a first dose of about 3 mg and a second dose of about 3 mg.

[0153] In some embodiments, the methods provided herein include administering two doses of about 3 mg encefentin (e.g., or a pharmaceutical composition containing encefentin) to a subject daily via inhalation. The methods may include administering about 3 mg encefentin (e.g., or a pharmaceutical composition containing encefentin) to a subject twice daily via inhalation (e.g., 3 mg BID). In some embodiments, the methods include administering a dose of about 3 mg encefentin (e.g., or a pharmaceutical composition containing encefentin) to a subject twice daily via a nebulizer. In some cases, each dose may contain 3.0 mg of encefentin free base administered via a nebulizer.

[0154] In some embodiments, encefentin (e.g., or a pharmaceutical composition containing encefentin) as described herein is used as maintenance therapy. In some embodiments, the methods described herein include administering the pharmaceutical composition to a subject at least once daily for at least 8 weeks. In some embodiments, the pharmaceutical composition may be administered to a subject at least once daily for at least 16 weeks. In some embodiments, the pharmaceutical composition may be administered to a subject at least once daily for at least 24 weeks. In some embodiments, the pharmaceutical composition may be administered to a subject daily for at least 1 year. The methods described herein may include administering the pharmaceutical composition to a subject at least once every 24 hours. In some cases, the method includes administering the pharmaceutical composition at least twice every 24 hours, for example, for at least 8, 16, or 24 weeks. In some embodiments, the pharmaceutical composition is administered to the subject for any suitable time period determined by a technician.

[0155] In some embodiments, encefentin is administered as a suspension. In some embodiments, encefentin is delivered as a dry powder, such as a dry powder containing particles of encefentin and particles of a carrier such as lactose. In some embodiments, the method described herein includes administering an inhalable pharmaceutical composition comprising a suspension of encefentin particles in a diluent.

[0156] As described herein, encefentin particles can be dispersed in a diluent (e.g., forming a suspension of particles in a diluent). The diluent may contain water or a buffer (e.g., a phosphate buffer). In some embodiments, the diluent contains water. In some embodiments, the diluent contains a buffer. In some embodiments, the diluent contains a phosphate buffer.

[0157] In some embodiments, encefentin particles may be dispersed in a sterile liquid medium. In some embodiments, the sterile liquid medium contains one or more diluents. In some embodiments, the sterile liquid medium contains only a single diluent, such as water.

[0158] While preferred embodiments of this disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, modifications, and substitutions will now occur to those skilled in the art without departing from this disclosure. It should be understood that various alternatives to the embodiments of this disclosure described herein can be used to practice this disclosure. The appended claims are intended to define the scope of this disclosure and thus cover the methods and structures within the scope of those claims and their equivalents. Example

[0159] Example 1: Encerfentin treatment in subjects with kidney or liver damage A clinical study was conducted to determine the efficacy of encefentin in treating COPD compared to placebo. Encefentin is administered via nebulizer at a dose of 3 mg twice daily (BID) for 24 weeks. This study was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial with approximately 800 patients and a 5:3 randomization.

[0160] The study population included patients aged 40–80 years with moderate to severe COPD (FEV1 30%–70% pn, FEV1 / FVC ratio <0.7, with mMRC ≥ 2). Randomization was stratified according to: (a) use of stable background maintenance LAMA or LABA therapy (approximately 50% yes or no), and (b) smoking (current or past). Inhaled corticosteroid (ICS) maintenance therapy was permitted in up to 20% of patients under certain conditions.

[0161] The primary endpoint of this study was the mean area under the curve (AUC) of FEV1 within 4 hours after the 12-week dose. 0-12h Changes from baseline; morning trough FEV1 at week 12; and other endpoints including the frequency of moderate / severe COPD exacerbations within 24 weeks.

[0162] method Baseline FEV1 is the average of two measurements taken before the study drug on the day of first dosing: ≤ 40 minutes before dosing and immediately before dosing, both before the dose on day 1. Mean FEV1 AUC 0-12h It is defined as the area under the curve of FEV1 over 12 hours divided by 12 hours.

[0163] Plasma concentrations of encefentin used to evaluate pharmacokinetic (PK) parameters were measured using a validated bioanalytical method for encefentin in human plasma with an LLOQ of 5 pg / mL. Samples were obtained according to the following schedule: Week 6: 1.0 hour (±0.5 hours) and 2.5 hours (±0.5 hours) (even-numbered stations) or 1.5 hours and 4 hours (±1 hour) (odd-numbered stations); • Week 12: Before dose (-0.5 hours), 4 to 6 hours and 8 to 12 hours (even-numbered sites) or 0.5 hours (±0.25 hours), 3 hours (±0.5 hours) and 6 to 8 hours (odd-numbered sites); • Week 24: Before dose (-0.5 hours) and 1.5 hours (even-numbered sites) or before dose (-0.5 hours) and 1 hour (±0.5 hours) (odd-numbered sites) preparation The investigational product and placebo were provided in ampoules as 2.5 mL unit doses and administered via nebulizer. The formulations of the investigational product (encefentin suspension containing crystalline polymorph type I) and placebo are shown in Table 2.

[0164] Table 2 Result—Kidney damage Satisfying the average FEV1AUC in week 12 0-12h The primary endpoint was determined. The results are shown in Table 3.

[0165] Table 3 Based on samples acquired during the trial, PK data from COPD patients with varying levels of renal function were modeled.

[0166] Model Using NONMEM® version 7.4.4, a two-compartment model with primary input and primary elimination from the central compartment was fitted to enstatin plasma concentration-time data. Different absorption functions and compartmental structures were explored. Inter-individual variability was incorporated into apparent plasma clearance (CL / F), volumes of the central and peripheral compartments (V2 / F and V3 / F, respectively), inter-compartmental clearance (Q / F), primary absorption rate (Ka), and relative bioavailability (F1). Residual variability was incorporated using a proportional error model, along with inter-individual variability (IIV) incorporated into the residual error and inter-case variability (IOV) incorporated into F1.

[0167] Initially, a first-order conditional estimation method with interactions (FOCE) was used, which frequently encountered numerical problems during minimization. Regarding the construction of the covariate model, considering the predominantly sparse nature of the dataset and the convergence issues with FOCE, the estimation method was switched to stochastic approximate expectation maximization (SAEM) to obtain parameter estimates, followed by importance sampling (IMP) to obtain the objective function value (OFV). Forward inclusion and backward elimination methods were performed (using goodness-of-fit plots, effect size, estimation precision, and OFV changes equivalent to p < 0.05 and p < 0.001, respectively) to evaluate the effects of covariates on CL / F, V2 / F, Q / F, V3 / F, Ka, and F1. Key covariates of interest included: disease state, weight, age, race, ethnicity, sex, renal function, liver function, liver enzymes, dose, and dosage form. Additional exploratory covariates were evaluated only when the plot of the Empirical Bayes Estimate (EBE) relative to the covariates suggested a moderate to large effect.

[0168] The final model was evaluated using goodness-of-fit plots, bootstrap analysis, and visual predictive test (VPC). Then, simulations were performed on selected covariates to further assess the clinical relevance found.

[0169] Results from the model Subjects with normal to mild renal impairment were defined as individuals with an absolute estimated glomerular filtration rate (aEGFR) greater than or equal to 60 mL / min. Subjects with moderate renal impairment were defined as individuals with an aEGFR less than 60 mL / min. A final popPK model was used to predict parameter estimates in a virtual population of 50,000 subjects (for each covariate condition) to simulate enstatin PK after 3 mg nebulization in a population reflecting those with normal or mild renal impairment, or those with moderate renal impairment, in the trial. Uncertainties in the fixed effects and covariance matrix parameters, as well as residual variability, were incorporated into the simulation. Parameter uncertainties were accounted for by creating 500 non-MEM simulation control flows in R by randomly resampling (without replay) 500 sets of parameter estimates from a bootstrapping method (750 replicates). From each set of parameter estimates, the pharmacokinetic profiles of 100 subjects (for each covariance condition) were simulated using the IIV and IOV from the covariance matrix and the residual error in NONMEM. Individual subject concentrations were simulated using NONMEM version 7.4.3, and pharmacokinetic parameters were calculated using R version 3.4.0. The results are shown in Table 4 and... Figure 1A -B and Figure 2 middle.

[0170] Table 4 Encerfentin has been found to provide statistically significant improvements in lung function in individuals with normal to mild renal impairment, as well as in subjects with moderate renal impairment. In subjects with moderate renal impairment, a C10 level of 604 pg / mL was achieved in patients with COPD. max And the mean AUC was 3200 pg / mL*h. These values ​​are lower than the mean C10 observed after the composition was administered to healthy patients. max (852 pg / mL) and mean AUC (5929 pg / mL*h mean AUC) 0-∞ The levels were also lower in patients with normal to mild renal impairment, indicating that systemic exposure to enstatin was lower in COPD patients than in healthy patients or those with normal to mild renal impairment.

[0171] Outcome—Liver damage In non-COPD subjects with and without liver impairment, the dose-normalized steady-state AUC of 3 mg dose was [value missing]. tau Showing Figure 3 In the middle. For example Figure 3 The AUC of healthy subjects described in the text tau,ss The AUC was approximately 5000 pg / mL*h to approximately 9000 pg / mL*h in subjects with moderate hepatic impairment. tau,ss The AUC was approximately 4000 pg / mL*h to approximately 11000 pg / mL*h in subjects with severe hepatic impairment. tau,ss The range was approximately 5500 pg / mL*h to approximately 6500 pg / mL*h. Exposure (AUC) in subjects with moderate (n=10) or severe (n=2) hepatic impairment was comparable to that in healthy subjects. The highest dose-normalized AUC observed in this subset is... tau,ss This was for subjects with moderate hepatic impairment, but it was not the highest exposure in the overall dataset, as it was exceeded by two other subjects with COPD. The results may suggest that ensifentin can be administered at similar doses to individuals with different levels of hepatic impairment (e.g., healthy, moderate, or severe hepatic impairment) resulting in similar PK profiles.

[0172] Implementation Plan Other implementation schemes include the following: 1. A method for treating chronic obstructive pulmonary disease (COPD) in a human subject with moderate renal impairment, the method comprising administering a liquid pharmaceutical composition to the human subject comprising a therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof.

[0173] 2. The method of implementation scheme 1, wherein the human subject has an absolute estimated glomerular filtration rate (aEGFR) of less than 60 mL / min.

[0174] 3. The method of any of the foregoing embodiments, wherein the liquid pharmaceutical composition provides a plasma concentration of enstatin after administration to a human subject by inhalation, the plasma concentration comprising an average C0.05 of about 500 pg / mL to about 700 pg / mL. max .

[0175] 4. The method of embodiment 3, wherein the plasma concentration comprises an average Cg of about 550 pg / mL to about 650 pg / mL. max .

[0176] 5. The method of embodiment 3 or 4, wherein the plasma concentration comprises an average Cg of approximately 604 pg / mL. max .

[0177] 6. The method of any one of implementation schemes 3-5, wherein C max Compared to subjects who received the liquid drug composition via inhalation and did not have moderate renal impairment, C max At least 10% higher.

[0178] 7. The method of any one of embodiments 3-6, wherein the plasma concentration comprises an average AUC of about 2600 pg / mL*h to about 3600 pg / mL*h. 0-tau .

[0179] 8. The method of embodiment 7, wherein the plasma concentration comprises an average AUC of about 3000 pg / mL*h to about 3400 pg / mL*h. 0-tau .

[0180] 9. The method of embodiment 7 or 8, wherein the plasma concentration comprises an average AUC of approximately 3200 pg / mL*h. 0-tau .

[0181] 10. The method of any one of embodiments 7-9, wherein the average AUC 0-tau The mean AUC of the liquid drug composition administered by inhalation to subjects without moderate renal impairment was compared with that of subjects who received the liquid drug composition by inhalation. 0-tau At least 25% higher.

[0182] 11. The method of any one of embodiments 3-10, wherein the plasma concentration comprises an average Tg of about 1 to 2 hours. max .

[0183] 12. The method of embodiment 11, wherein the plasma concentration comprises an average Tg of about 1.2 hours to about 1.7 hours. max .

[0184] 13. The method of any one of embodiments 1-12, wherein the average C max Average AUC 0-tau and average T max Measurements were taken at intervals, including two or more of the following: 1.0 hour (±0.5 hours), 1.5 hours (±0.5 hours), 2.5 hours (±0.5 hours), 3.0 hours (±0.5 hours), 4.0 hours (±1 hour), 6.0 hours (±1 hour), 8.0 hours (±1 hour), 10.0 hours (±1 hour), 12.0 hours (±1 hour), 24.0 hours (±1 hour), 36.0 hours (±1 hour), 48.0 hours (±1 hour), 56.0 hours (±1 hour), and 60.0 hours (±1 hour) after administration of the liquid pharmaceutical composition.

[0185] 14. A method for treating chronic obstructive pulmonary disease (COPD) in a human subject, the subject having liver function including healthy liver function, moderate liver impairment, or severe liver impairment, the method comprising administering to the human subject a liquid pharmaceutical composition comprising a therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof. The liquid pharmaceutical composition described herein provides plasma concentrations of encefentanyl containing AUCt,ss that are substantially the same for subjects with healthy liver function, moderate liver impairment, or severe liver impairment.

[0186] 15. The method of implementation scheme 14, wherein the average AUC t,ss From approximately 5000 pg / mL*h to approximately 10000 pg / mL*h.

[0187] 16. The method of implementation scheme 14 or 15, wherein the average AUC t,ss It ranges from approximately 5000 pg / mL*h to approximately 7500 pg / mL*h.

[0188] 17. The method of any one of embodiments 14-16, wherein the liver function of the human subject is classified using the Child-Pugh score.

[0189] 18. The method of any one of embodiments 14-17, wherein the administration is performed by inhalation.

[0190] 19. The method of any one of embodiments 3-13 or 18, wherein the inhalation is performed via a nebulizer.

[0191] 20. The method of any of the foregoing embodiments, wherein the encefentin is an encefentin free base.

[0192] 21. The method of any of the foregoing embodiments, wherein the administration to the human subject is at least once, twice, or three times daily.

[0193] 22. The method of any of the foregoing embodiments, wherein the administration to the human subject is at least twice daily.

[0194] 23. The method of any of the foregoing embodiments, wherein the therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof is about 2 mg to about 4 mg.

[0195] 24. The method of implementation scheme 23, wherein the therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof is 3 mg.

[0196] 25. The method of any of the foregoing embodiments, wherein the therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof comprises a total daily dose of about 0.5 mg to about 10 mg of encefentin or a pharmaceutically acceptable salt thereof.

[0197] 26. The method of embodiment 25, wherein the total daily dose is about 5 mg to about 7 mg.

[0198] 27. The method of any of the foregoing embodiments, wherein administration to the human subject comprises a first dose and a second dose per day.

[0199] 28. The method of embodiment 27, wherein the first dose comprises about 2 mg to about 4 mg of encefentin or a pharmaceutically acceptable salt thereof, and the second dose comprises about 2 mg to about 4 mg of encefentin or a pharmaceutically acceptable salt thereof.

[0200] 29. The method of embodiment 27, wherein the first and second doses comprise about 3 mg of encefentin or a pharmaceutically acceptable salt thereof.

[0201] 30. The method of any one of embodiments 27-29, wherein the first dose is administered in the morning and the second dose is administered in the evening.

[0202] 31. The method of any one of embodiments 27-29, wherein the first dose is administered within three hours after the human subject wakes up, and the second dose is administered within three hours before the human subject goes to sleep.

[0203] 32. The method of any one of embodiments 27-29, wherein the first dose and the second dose are administered to a human subject about 10 hours to about 14 hours apart.

[0204] 33. The method of any of the foregoing embodiments, wherein the administration to the human subject is twice daily for at least 8 weeks.

[0205] 34. The method of any of the foregoing embodiments, wherein the administration to the human subject is twice daily for at least 16 weeks.

[0206] 35. The method of any of the foregoing embodiments, wherein the administration to the human subject is twice daily for at least 24 weeks.

[0207] 36. The method of any of the foregoing embodiments, wherein the liquid pharmaceutical composition comprises a suspension of encefentin granules, which contains encefentin or a pharmaceutically acceptable salt thereof in a diluent.

[0208] 37. The method of embodiment 36, wherein the encefentin granules contain at least 95% by weight encefentin or a pharmaceutically acceptable salt thereof.

[0209] 38. The method of embodiment 36, wherein the encefentin particles comprise at least 95% encefentin free base by weight.

[0210] 39. The method of any one of embodiments 36-38, wherein the encefentin is in crystalline solid form, the crystalline solid consisting of more than 99% by weight of encefentin free base. At least 95% of the product is in the polymorphic form of the thermodynamically stable polymorph (I) of the encefentin free base, which has the following structural parameters obtained by single-crystal analysis: wavelength 0.71073 Å Crystal system Triclinic crystal system Space Group P-1 Cell size a = 8.1246(4)Å α = 91.583（4）° b = 11.4573 (5) Å ß =90.299（4）° c = 13.2398(6)Å γ = 99.628(4)° volume <![CDATA[1214.56(10)Å 3 ]]> Z 2 40. The method of any one of embodiments 36-39, wherein the encefentin granules contain about 0% to about 0.6% by weight of 1,3-bis(2-(2-(trimethylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (BMIQU) relative to the total weight of encefentin or a pharmaceutically acceptable salt thereof.

[0211] 41. The method of any one of embodiments 36-40, wherein the encefentin granules contain about 0% to about 0.5% by weight of a biuret impurity of formula (A) relative to the total weight of encefentin or a pharmaceutically acceptable salt thereof: .

[0212] 42. The method of embodiment 41, wherein the encefentin granules contain about 0% to about 0.3% by weight of biuret impurities relative to the total weight of encefentin or a pharmaceutically acceptable salt thereof.

[0213] 43. The method of any one of embodiments 40-42, wherein the encefentin granules contain about 0.01% to about 0.3% by weight of BMIQU relative to the total weight of encefentin or a pharmaceutically acceptable salt thereof.

[0214] 44. The method of any one of embodiments 36-43, wherein the liquid pharmaceutical composition comprises: (a) Encefentin granules; (b) Buffer; (c) One or more surfactants; and (d) Tension regulator.

[0215] 45. The method of any one of embodiments 36-44, wherein the liquid pharmaceutical composition comprises: (a) Encerfentin granules with a concentration of about 1 mg / mL to about 1.4 mg / mL; (b) Buffers with a concentration of about 1 mg / mL to about 2 mg / mL; (c) One or more surfactants with a total concentration of about 0.01 mg / mL to about 0.8 mg / mL; and (d) A tension modulator at a concentration of about 5 mg / mL to about 10 mg / mL.

[0216] 46. ​​The method of any one of embodiments 36-45, wherein the liquid pharmaceutical composition comprises: (a) Encerfentin granules with a concentration of about 1 mg / mL to about 1.4 mg / mL; (b) Polysorbate 20 (Tween 20) at a concentration of about 0.3 mg / mL to about 0.7 mg / mL; (c) Span20, anhydrous sorbitan monolaurate at a concentration of 0 mg / mL to about 0.1 mg / mL. (d) Sodium dihydrogen phosphate dihydrate at a concentration of about 0.5 mg / mL to about 1 mg / mL; (e) Disodium hydrogen phosphate dihydrate at a concentration of about 0.5 mg / mL to about 1 mg / mL; and (f) Sodium chloride at a concentration of about 5 mg / mL to about 10 mg / mL.

[0217] 47. The method of any one of embodiments 36-46, wherein the liquid pharmaceutical composition comprises: (a) Encefentin granules with a concentration of 1.2 mg / mL; (b) Polysorbate 20 (Tween 20) at a concentration of 0.5 mg / mL; (c) Span 20, anhydrous sorbitol monolaurate at a concentration of 0.05 mg / mL; (d) Sodium dihydrogen phosphate dihydrate at a concentration of 0.744 mg / mL; (e) Disodium hydrogen phosphate dihydrate at a concentration of 0.853 mg / mL; and (f) Sodium chloride at a concentration of 8.6 mg / mL.

[0218] 48. The method of any one of embodiments 36-46, wherein the liquid pharmaceutical composition is a suspension comprising: (a) 1.4 mg / mL Encefentin granules; (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.

[0219] 49. The method of any one of embodiments 36-46, wherein the liquid pharmaceutical composition is a suspension comprising: (a) 1.3 mg / mL Encefentin granules; (b) 0.55 mg / ml sorbitol 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.

[0220] 50. The method of any one of embodiments 36-44, wherein the liquid pharmaceutical composition is a suspension comprising: (a) 1.3 mg / mL Encefentin granules; (b) 0.5 mg / ml polysorbate 20; (c) 0.05 mg / ml sorbitol 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.

[0221] 51. The method of any one of embodiments 36-46, wherein the liquid pharmaceutical composition is a suspension comprising: (a) 1.2 mg / mL Encefentin granules; (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.

[0222] 52. The method of any one of embodiments 36-46, wherein the liquid pharmaceutical composition is a suspension comprising: (a) 1.4 mg / mL Encefentin granules; (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.

[0223] 53. The method of any one of embodiments 36-46, wherein the liquid pharmaceutical composition comprises: (a) Encefentin granules with a concentration of 0.8 to 1.4 mg / mL; (b) One or more surfactants with 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 a concentration of 1.0 to 15.0 mg / ml, and (e) Water.

[0224] 54. The method of any one of embodiments 45-53, wherein the total weight of encefentin or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical composition is about 2.7 mg to about 3.3 mg.

[0225] 55. The method of any of the foregoing embodiments, wherein the encefentin or a pharmaceutically acceptable salt thereof is used in combination with a muscarinic receptor antagonist, a β-adrenergic receptor agonist, or an inhaled glucocorticoid.

[0226] 56. The method of any of the foregoing embodiments, wherein the COPD is moderate COPD.

[0227] 57. The method of any one of embodiments 1-55, wherein the COPD is severe COPD.

[0228] 58. Use of any one of the methods in Implementation Schemes 1-57 for the treatment of chronic obstructive pulmonary disease (COPD) in human subjects.

[0229] * * * While the foregoing refers to specific preferred embodiments, it should be understood that the invention 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 contemplated within the scope of the invention.

[0230] All publications, patent applications and patents cited in this specification are incorporated herein by reference in their entirety.

Claims

1. A method for treating chronic obstructive pulmonary disease (COPD) in a human subject with moderate renal impairment, the method comprising administering a liquid pharmaceutical composition to the human subject comprising a therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the human subject has an absolute estimated glomerular filtration rate (aEGFR) of less than 60 mL / min.

3. The method according to any one of the preceding claims, wherein the liquid pharmaceutical composition provides a plasma concentration of enstatin after administration to a human subject by inhalation, said plasma concentration comprising an average C0.05 of about 500 pg / mL to about 700 pg / mL. max .

4. The method of claim 3, wherein the plasma concentration comprises an average Cg of about 550 pg / mL to about 650 pg / mL. max .

5. The method according to claim 3 or 4, wherein the plasma concentration comprises an average Cg of about 604 pg / mL. max .

6. The method according to any one of claims 3-5, wherein C max Compared to subjects who received the liquid drug composition via inhalation and did not have moderate renal impairment, C max At least 10% higher.

7. The method according to any one of claims 3-6, wherein the plasma concentration comprises an average AUC of about 2600 pg / mL*h to about 3600 pg / mL*h. 0-tau .

8. The method of claim 7, wherein the plasma concentration comprises an average AUC of about 3000 pg / mL*h to about 3400 pg / mL*h. 0-tau .

9. The method of claim 7 or 8, wherein the plasma concentration comprises an average AUC of about 3200 pg / mL*h. 0-tau .

10. The method according to any one of claims 7-9, wherein the average AUC 0-tau The mean AUC of the liquid drug composition administered by inhalation to subjects without moderate renal impairment was compared with that of subjects who received the liquid drug composition by inhalation. 0-tau At least 25% higher.

11. The method according to any one of claims 3-10, wherein the plasma concentration comprises an average Tg of about 1 to 2 hours. max .

12. The method of claim 11, wherein the plasma concentration comprises an average Tg of about 1.2 hours to about 1.7 hours. max .

13. The method according to any one of claims 1-12, wherein the average C max Average AUC 0-tau and average T max Measurements were taken at intervals, including two or more of the following: 1.0 hour (±0.5 hours), 1.5 hours (±0.5 hours), 2.5 hours (±0.5 hours), 3.0 hours (±0.5 hours), 4.0 hours (±1 hour), 6.0 hours (±1 hour), 8.0 hours (±1 hour), 10.0 hours (±1 hour), 12.0 hours (±1 hour), 24.0 hours (±1 hour), 36.0 hours (±1 hour), 48.0 hours (±1 hour), 56.0 hours (±1 hour), and 60.0 hours (±1 hour) after administration of the liquid pharmaceutical composition.

14. A method for treating chronic obstructive pulmonary disease (COPD) in a human subject, the subject having liver function including healthy liver function, moderate liver impairment, or severe liver impairment, the method comprising administering to the human subject a liquid pharmaceutical composition comprising a therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof. The liquid pharmaceutical composition described herein provides plasma concentrations of encefentanyl containing AUCt,ss that are substantially the same for subjects with healthy liver function, moderate liver impairment, or severe liver impairment.

15. The method of claim 14, wherein the average AUC t,ss From approximately 5000 pg / mL*h to approximately 10000 pg / mL*h.

16. The method of claim 14 or 15, wherein the average AUC t,ss It ranges from approximately 5000 pg / mL*h to approximately 7500 pg / mL*h.

17. The method according to any one of claims 14-16, wherein the liver function of the human subject is classified using the Child-Pugh score.

18. The method according to any one of claims 14-17, wherein the administration is performed by inhalation.

19. The method according to any one of claims 3-13 or 18, wherein the inhalation is performed via a nebulizer.

20. The method according to any one of the preceding claims, wherein the encefentin is an encefentin free base.

21. The method according to any one of the preceding claims, wherein the administration to the human subject is at least once, twice, or three times daily.

22. The method according to any one of the preceding claims, wherein the administration to the human subject is at least twice daily.

23. The method according to any one of the preceding claims, wherein the therapeutically effective amount of said encefentin or a pharmaceutically acceptable salt thereof is about 2 mg to about 4 mg.

24. The method of claim 23, wherein the therapeutically effective amount of encefentin or a pharmaceutically acceptable salt thereof is 3 mg.

25. The method according to any one of the preceding claims, wherein the therapeutically effective amount of said encefentin or a pharmaceutically acceptable salt thereof comprises a total daily dose of about 0.5 mg to about 10 mg of encefentin or a pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein the total daily dose is about 5 mg to about 7 mg.

27. The method according to any one of the preceding claims, wherein administration to the human subject comprises a first dose and a second dose per day.

28. The method of claim 27, wherein the first dose comprises about 2 mg to about 4 mg of encefentin or a pharmaceutically acceptable salt thereof, and the second dose comprises about 2 mg to about 4 mg of encefentin or a pharmaceutically acceptable salt thereof.

29. The method of claim 27, wherein the first dose and the second dose comprise about 3 mg of encefentin or a pharmaceutically acceptable salt thereof.

30. The method according to any one of claims 27-29, wherein the first dose is administered in the morning and the second dose is administered in the evening.

31. The method according to any one of claims 27-29, wherein the first dose is administered within three hours after the human subject wakes up, and the second dose is administered within three hours before the human subject goes to sleep.

32. The method according to any one of claims 27-29, wherein the first dose and the second dose are administered to a human subject at intervals of about 10 hours to about 14 hours.

33. The method according to any one of the preceding claims, wherein the administration to the human subject is twice daily for at least 8 weeks.

34. The method according to any one of the preceding claims, wherein the administration to the human subject is twice daily for at least 16 weeks.

35. The method according to any one of the preceding claims, wherein the administration to the human subject is twice daily for at least 24 weeks.

36. The method according to any one of the preceding claims, wherein the liquid pharmaceutical composition comprises a suspension of encefentin granules, which contains encefentin or a pharmaceutically acceptable salt thereof in a diluent.

37. The method of claim 36, wherein the encefentin granules comprise at least 95% by weight encefentin or a pharmaceutically acceptable salt thereof.

38. The method of claim 36, wherein the encefentin particles comprise at least 95% encefentin free base by weight.

39. The method according to any one of claims 36-38, wherein the encefentin is in crystalline solid form, the crystalline solid comprising greater than 99% by weight of encefentin free base. At least 95% of the product is in the polymorphic form of the thermodynamically stable polymorph (I) of the encefentin free base, which has the following structural parameters obtained by single-crystal analysis: 。 40. The method according to any one of claims 36-39, wherein the encefentin granules contain about 0% to about 0.6% by weight of 1,3-bis(2-(2-(trimethylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimidino[6,1-a]isoquinoline-3(4H)-yl)ethyl)urea (BMIQU) relative to the total weight of encefentin or a pharmaceutically acceptable salt thereof.

41. The method according to any one of claims 36-40, wherein the encefentin granules contain about 0% to about 0.5% by weight of a biuret impurity of formula (A) relative to the total weight of encefentin or a pharmaceutically acceptable salt thereof: 。 42. The method of claim 41, wherein the encefentin granules contain about 0% to about 0.3% by weight of biuret impurities relative to the total weight of encefentin or a pharmaceutically acceptable salt thereof.

43. The method according to any one of claims 40-42, wherein the encefentin granules contain about 0.01% to about 0.3% by weight of BMIQU relative to the total weight of encefentin or a pharmaceutically acceptable salt thereof.

44. The method according to any one of claims 36-43, wherein the liquid pharmaceutical composition comprises: (a) Encefentin granules; (b) Buffer; (c) One or more surfactants; and (d) Tension regulator.

45. The method according to any one of claims 36-44, wherein the liquid pharmaceutical composition comprises: (a) Encerfentin granules with a concentration of about 1 mg / mL to about 1.4 mg / mL; (b) Buffers with a concentration of about 1 mg / mL to about 2 mg / mL; (c) One or more surfactants with a total concentration of about 0.01 mg / mL to about 0.8 mg / mL; and (d) A tension modulator at a concentration of about 5 mg / mL to about 10 mg / mL.

46. ​​The method according to any one of claims 36-45, wherein the liquid pharmaceutical composition comprises: (a) Encerfentin granules with a concentration of about 1 mg / mL to about 1.4 mg / mL; (b) Polysorbate 20 (Tween 20) at a concentration of about 0.3 mg / mL to about 0.7 mg / mL; (c) Span 20, anhydrous sorbitan monolaurate at a concentration of 0 mg / mL to about 0.1 mg / mL; (d) Sodium dihydrogen phosphate dihydrate at a concentration of about 0.5 mg / mL to about 1 mg / mL; (e) Disodium hydrogen phosphate dihydrate at a concentration of about 0.5 mg / mL to about 1 mg / mL; and (f) Sodium chloride at a concentration of about 5 mg / mL to about 10 mg / mL.

47. The method according to any one of claims 36-46, wherein the liquid pharmaceutical composition comprises: (a) Encefentin granules with a concentration of 1.2 mg / mL; (b) Polysorbate 20 (Tween 20) at a concentration of 0.5 mg / mL; (c) Span 20, anhydrous sorbitol monolaurate at a concentration of 0.05 mg / mL; (d) Sodium dihydrogen phosphate dihydrate at a concentration of 0.744 mg / mL; (e) Disodium hydrogen phosphate dihydrate at a concentration of 0.853 mg / mL; and (f) Sodium chloride at a concentration of 8.6 mg / mL.

48. The method according to any one of claims 45-47, wherein the total weight of encefentin or a pharmaceutically acceptable salt thereof in the liquid pharmaceutical composition is about 2.7 mg to about 3.3 mg.

49. The method according to any one of the preceding claims, wherein the encefentin or a pharmaceutically acceptable salt thereof is used in combination with a muscarinic receptor antagonist, a β-adrenergic receptor agonist, or an inhaled glucocorticoid.

50. The method according to any one of the preceding claims, wherein the COPD is moderate COPD.

51. The method according to any one of claims 1-49, wherein the COPD is severe COPD.

52. Use of the method according to any one of claims 1-51 for treating chronic obstructive pulmonary disease (COPD) in a human subject.

53. The method according to any one of claims 36-44, wherein the liquid pharmaceutical composition is a suspension comprising: a. 1.4 mg / mL Encefentin granules; 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.

54. The method according to any one of claims 36-46, wherein the liquid pharmaceutical composition is a suspension comprising: a. 1.3 mg / mL Encefentin granules; b. 0.55 mg / ml sorbitol 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.

55. The method according to any one of claims 36-44, wherein the liquid pharmaceutical composition is a suspension comprising: a. 1.3 mg / mL Encefentin granules; b. 0.5 mg / ml polysorbate 20; c. 0.05 mg / ml sorbitol 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.

56. The method according to any one of claims 36-46, wherein the liquid pharmaceutical composition is a suspension comprising: a. 1.2 mg / mL Encefentin granules; 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.

57. The method according to any one of claims 36-46, wherein the liquid pharmaceutical composition is a suspension comprising: a. 1.4 mg / mL Encefentin granules; 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.

58. The method according to any one of claims 36-46, wherein the liquid pharmaceutical composition comprises: a. Encerfentin granules with a concentration of 0.8 to 1.4 mg / mL; b. One or more surfactants with 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 a concentration of 1.0 to 15.0 mg / ml, and e. Water.

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