Liquid pharmaceutical composition

Abstract

The present invention relates to a liquid pharmaceutical composition comprising a dose of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the liquid pharmaceutical composition provides a plasma concentration of ensifentrine after administration by inhalation to a human subject with COPD, the plasma concentration of ensifentrine having a mean C of about 400 pg / mL to about 720 pg / mL. max and / or approximately 2000 pg / mL * h to approximately 3000 pg / mL * Mean AUC of h 0-tau and / or a mean T of about 0.6 hours to about 1.5 hours max The present invention also provides a method of treating COPD.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a liquid pharmaceutical composition comprising a dose of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Background of the Invention Ensifentrine (N-(2-{(2E)-9,10-dimethoxy-4-oxo-2-[(2,4,6-trimethylphenyl)imino]-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-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 combined PDE3 / PDE4 inhibitor, ensifentrine has both bronchodilator and anti-inflammatory activity and is useful in the treatment of respiratory disorders, including chronic obstructive pulmonary disease (COPD). The chemical structure of ensifentrine is shown below.

[0004] [ka]

[0005] COPD is a progressive, long-term condition. Ensifentrine is typically administered to COPD patients by nebulizer as a maintenance therapy. It would be beneficial to provide a plasma concentration of ensifentrine with a desirable pharmacokinetic profile in COPD patients following inhalation of a liquid pharmaceutical composition suitable for inhalation. Summary of the Invention

[0006] It has been discovered that a liquid pharmaceutical composition comprising a dose of ensifentrine or a pharmaceutically acceptable salt thereof can provide advantageous plasma concentrations of ensifentrine following inhalation in a human subject with COPD.

[0007] The present invention therefore provides a liquid pharmaceutical composition comprising a dose of a compound that is ensifentrine or a pharmaceutically acceptable salt thereof, wherein the liquid pharmaceutical composition, after administration by inhalation to a human subject with COPD, provides a plasma concentration of ensifentrine that is: Mean C of approximately 400 pg / mL to approximately 720 pg / mL max and / or Approximately 2000pg / mL * h to approximately 3000 pg / mL * Mean AUC of h 0-tau and / or Average T of approximately 0.6 to 1.5 hours max It has.

[0008] The present invention also provides an ampoule containing the liquid pharmaceutical composition. Further provided by the present invention is a nebulizer containing the liquid pharmaceutical composition.

[0009] Also provided by the present invention is a method of treating COPD in a human subject, the method comprising administering to the human subject by inhalation a liquid pharmaceutical composition. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description of the Invention The liquid pharmaceutical composition provides a plasma concentration of ensifentrine after administration by inhalation to a human subject with COPD, the plasma concentration of ensifentrine having a mean C of about 400 pg / mL to about 720 pg / mL. max and / or approximately 2000 pg / mL * h to approximately 3000 pg / mL * Mean AUC of h 0-tau and / or a mean T of about 0.6 hours to about 1.5 hours max As such, the liquid pharmaceutical composition is suitable for providing a plasma concentration of ensifentrine following administration by inhalation, for example, from a nebulizer, to a human subject with COPD.

[0011] C max , AUC 0-tau and T max is a pharmacokinetic parameter well known to those skilled in the art. max is the maximum concentration of the compound in plasma achieved following administration of the compound. max is C max 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 of time. AUC 0-tau is the AUC from administration to the end of the administration period (which may be, for example, 8 hours, 12 hours, or 24 hours). As used herein, tau is typically 12 hours, and AUC 0-tau is AUC 0-12h is.

[0012] Typically, the liquid pharmaceutical composition has a mean C of about 400 pg / mL to about 720 pg / mL after administration by inhalation to human subjects with COPD. max The plasma concentrations of ensifentrine having the mean C max can be about 500 pg / mL to about 600 pg / mL. For example, the mean C max can be from about 500 pg / mL to about 550 pg / mL, or from about 520 pg / mL to about 525 pg / mL.

[0013] Typically, the liquid pharmaceutical composition has a concentration of about 2000 pg / mL after administration by inhalation to a human subject with COPD. * h to approximately 3000 pg / mL * Mean AUC of h 0-tau The plasma concentrations of ensifentrine having a mean AUC 0-tau is approximately 2300 pg / mL * h to approximately 2600 pg / mL * h. For example, the average AUC 0-tau is approximately 2400 pg / mL * h to approximately 2500 pg / mL * h, or approximately 2425 pg / mL * h to approximately 2475 pg / mL* h.

[0014] The liquid pharmaceutical composition has a mean C of about 400 pg / mL to about 720 pg / mL after administration by inhalation to human subjects with COPD. max and approximately 2000 pg / mL * h to approximately 3000 pg / mL * Mean AUC of h 0-tau The plasma concentration of ensifentrine having the following formula may be provided:

[0015] Typically, the liquid pharmaceutical composition has a mean T of about 0.6 hours to about 1.5 hours after inhalation by a human subject with COPD. max The plasma concentrations of ensifentrine having mean T max For example, the average T max may be from about 0.9 hours to about 1.1 hours, from about 0.95 hours to about 1.05 hours.

[0016] The liquid pharmaceutical composition may provide, after administration by inhalation to a human subject with COPD, a plasma concentration of ensifentrine of: about 500 pg / mL to about 600 pg / mL mean C max and approximately 2300 pg / mL * h to approximately 2600 pg / mL * Mean AUC of h 0-tau and a mean T of about 0.8 hours to about 1.3 hours max The plasma concentrations of ensifentrine are: about 510 pg / mL to about 530 pg / mL mean C max and approximately 2350 pg / mL * h to approximately 3550 pg / mL * Mean AUC of h 0-tau and a mean T of about 0.9 hours to about 1.1 hours max may have:

[0017] As used herein, the term "about" may refer to a ±10% variation of the stated value.

[0018] The mean profile of the plasma concentration provided in human subjects with COPD can be determined based on the observed mean plasma concentrations of ensifentrine following administration of the liquid pharmaceutical composition by inhalation to a sample of human subjects with COPD. Typically, the mean C max , average AUC 0-tau and average T max is measured by determining plasma concentrations in a sample of human subjects with COPD at regular intervals after administration of the liquid pharmaceutical composition. The sample of human subjects may include 100 to 1000 human subjects, for example, 300 human subjects. The human subjects in the sample may range in age from 45 to 75 years old.

[0019] Those skilled in the art will know appropriate intervals for measuring plasma concentrations following inhalation of a liquid pharmaceutical composition. Typically, the intervals are two or more of the following after administration of the liquid pharmaceutical composition: -0.5 hours (±0.5 hours, i.e., before administration), 0.5 hours (±0.25 hours), 1.0 hours (±0.5 hours), 1.5 hours (±0.5 hours), 2.0 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). The intervals can be two or more of -0.5 hours (±0.5 hours, i.e., before administration), 1.0 hours (±0.5 hours), 2.0 hours (±0.5 hours), 3.0 hours (±0.5 hours), 4.0 hours (±1 hour), 12.0 hours (±1 hour), 24.0 hours (±1 hour), 36.0 hours (±1 hour), 48.0 hours (±1 hour), and 56.0 hours (±1 hour) after administration of the liquid pharmaceutical composition. For example, the intervals can be -0.5 hours (±0.5 hours, i.e., before administration), 0.5 hours (±0.25 hours), 1.0 hours (±0.5 hours), 2.0 hours (±0.5 hours), 3.0 hours (±0.5 hours), 4.0 hours (±1 hour), and 12.0 hours (±1 hour).

[0020] Typically, plasma concentrations are determined using an analytical method with an LLOQ of about 5.0 pg / mL or less.

[0021] Administration of a liquid pharmaceutical composition to a human subject by inhalation typically involves administration of the liquid pharmaceutical composition to a human subject by inhalation from a nebulizer. The nebulizer aerosolizes the liquid pharmaceutical composition into an aerosol that is inhaled into the respiratory tract of the human subject. Examples of nebulizers include soft mist nebulizers, vibrating mesh nebulizers, jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include Philips I-neb™ (Philips), Philips SideStream (Philips), AeroNeb® (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERxR™ Pulmonary Delivery System (Aradigm Corp), and Pari LC Plus Reusable Nebulizer (Pari GmbH). The nebulizer may be, for example, a PARI LC Sprint jet nebulizer with a PARI Vios® PRO Aerosol Delivery System PARI BOY® compressor. The liquid pharmaceutical composition may be inhaled through the nebulizer for 1 to 15 minutes, for example, 5 to 10 minutes.

[0022] For example, the average C max , average AUC 0-tau and average T max can be measured by determining the mean plasma concentration in a sample of 300 human subjects with COPD at regular intervals after administration of a liquid pharmaceutical composition, wherein the human subjects in the sample can have an age range of 45 to 75 years old, and the liquid pharmaceutical composition can be inhaled via a nebulizer for 1 to 15 minutes (e.g., about 7 minutes). The human subjects can have moderate COPD.

[0023] Human subjects typically receive the compound as maintenance therapy.The compound can be administered to human subjects once, twice or three times a day.Preferably, the compound is administered twice a day as maintenance therapy.

[0024] The liquid pharmaceutical composition comprises a compound dose of ensifentrine or its pharmaceutically acceptable salt.Typically, the dose is about 2 mg to about 4 mg of the compound.For example, the dose can be 2.5 mg to 3.5 mg of the compound.The dose can be 2.8 mg to 3.2 mg of the compound.The dose is typically about 3 mg of the compound, for example, about 3.0 mg.

[0025] The dose can be 2.8 mg to 3.2 mg of ensifentrine (i.e., ensifentrine free base). The dose is typically about 3 mg of ensifentrine, for example, 3.0 mg of ensifentrine.

[0026] The concentration of the compound in the liquid pharmaceutical composition is typically 0.8 to 1.6 mg / mL. For example, the liquid pharmaceutical composition typically contains ensifentrine at a concentration of 1.0 to 1.4 mg / mL. The liquid pharmaceutical composition may contain ensifentrine at a concentration of 1.1 to 1.3 mg / mL. The liquid pharmaceutical composition may contain about 1.2 mg / mL of ensifentrine.

[0027] Inhalation of a liquid pharmaceutical composition typically involves inhalation of only a portion of the liquid pharmaceutical composition. As such, only a portion of the liquid pharmaceutical composition is typically delivered to a patient, for example, due to the remainder of the liquid pharmaceutical composition remaining in the nebulizer used to deliver the liquid pharmaceutical composition by inhalation. The portion of the liquid pharmaceutical composition delivered from a nebulizer to a patient's lungs can be 20 to 40% by volume of the liquid pharmaceutical composition originally present in the nebulizer before administration. The portion of the liquid pharmaceutical composition delivered from a nebulizer to a patient's lungs can be 25 to 35% by volume, for example, 29 to 33% by volume, or about 31% by volume of the liquid pharmaceutical composition originally present in the nebulizer before administration. As such, the average delivered dose of the compound inhaled by a human subject is typically 20 to 40%, 25 to 35%, or 29 to 33% of the total dose present in the liquid pharmaceutical composition before administration. The average delivered dose of the compound (e.g., the average delivered dose of ensifentrine free base) is typically 0.7 to 1.1 mg when administered using a nebulizer. The average delivered dose may be 0.8 to 1.0 mg, for example 0.90 to 0.95 mg. The nebulizer is typically a jet nebulizer. Liquid pharmaceutical compositions typically have an average C as defined herein following delivery from the nebulizer. max , average AUC 0-tau and average T max Suitable for providing

[0028] The present invention also provides a liquid pharmaceutical composition as defined herein, which when administered using a nebulizer, provides an average delivered dose of the compound of 0.7 to 1.1 mg, which may be 0.8 to 1.0 mg, for example 0.90 to 0.95 mg.

[0029] Liquid pharmaceutical compositions typically provide an average increase in baseline FEV1 of at least 20mL after inhalation administration to human subjects.For example, liquid pharmaceutical compositions can provide an average increase in baseline FEV1 of at least 30mL after inhalation administration to human subjects.Typically, FEV1 used herein is determined as presented in the paper Standardization of spirometry, Eur J 2005; 26; 319-338.

[0030] Liquid pharmaceutical compositions typically comprise (a) a suspension of particles comprising compound and (b) a diluent.Diluent is typically water.It may be true that some or all of the particles comprising compound in liquid pharmaceutical compositions will settle to the bottom of the container that contains the liquid pharmaceutical composition, for example, after a period of storage.The particles comprising compound can be resuspended by any suitable method, for example, by stirring the sterile liquid pharmaceutical composition.

[0031] The particles containing the compound typically have a Dv50 of about 0.2 μm to about 5.0 μm. For example, the particles containing the compound may have a Dv50 of about 1.0 μm to about 2.2 μm, or about 1.1 μm to about 1.5 μm.

[0032] Particle size is described herein with reference to the Dv50 value, which is the median particle size for volume distribution. That is, half of the particle volume has a diameter smaller than the Dv50 value, and half of the particle volume has a diameter larger than the Dv50 value. This is a well-known method for describing particle size distribution. Dv10 and Dv90 parameters can also be used to characterize the particle size distribution of a sample. 10% of the particle volume has a diameter smaller than the Dv10 value. 90% of the particle volume has a diameter smaller than the Dv90 value.

[0033] Particles comprising the compound typically have a Dv10 of about 0.3 μm to about 0.9 μm and / or a Dv90 of about 2.3 μm to about 4.5 μm.

[0034] For example, particles comprising the compound may have: a Dv10 of about 0.3 μm to about 0.9 μm; and a Dv50 of about 1.0 μm to about 2.2 μm; and a Dv90 of about 2.3 μm to about 4.5 μm.

[0035] The technique used to measure Dv10, Dv50 and Dv90 values ​​described herein is typically laser diffraction.The particle size distribution of particles comprising compound can be measured by laser diffraction using wet powder dispersion system.For example, particle size distribution can be measured by laser diffraction using Malvern Spraytec connected with wet dispersion cell.Typically, the instrument parameters for Malvern Spraytec are as follows:

[0036] · Particles – standard opaque particles; · Refractive index particles - 1.50; · Refractive index (imaginary) -0.50; · Particle density -1.00; · Refractive index of the dispersant - 1.33; Controller unit - 1000RPM; Measurement type - timed; Initial sampling time - 30 seconds; · Shading - 20%-30%; Dispersant - 1% Polysorbate 20 in deionized water.

[0037] The ensifentrine particles can be produced by any pharmaceutically acceptable size reduction process or particle size controlled manufacturing process. For example, the particles can be produced by spray drying a solution of ensifentrine, by controlled crystallization, or by size reduction of ensifentrine in solid form, such as by air jet milling, mechanical micronization, or media milling.

[0038] The compound-containing particles typically contain ensifentrine (i.e., ensifentrine free base). The particles may contain at least 90% by weight of ensifentrine free base, for example, at least 95% by weight of ensifentrine, based on the total weight of the particle. The particles may contain at least 99% by weight of ensifentrine. The particles may consist of ensifentrine.

[0039] The compound is typically in a crystalline form. The particles containing the compound typically contain at least 90% by weight of ensifentrine free base Form I relative to the total weight of the particles. Ensifentrine free base Form I is a crystalline polymorph of ensifentrine (crystalline polymorph Form I) that typically has a powder X-ray diffraction pattern including characteristic peaks at 10.1° and 12.9°±0.1°2θ. The values ​​of °2θ described herein are typically as measured using the X-ray wavelength of CuKα radiation (λ=1.5406Å). The powder X-ray diffraction pattern of Form I typically further includes characteristic peaks at 15.3° and 17.6°±0.1°2θ. Ensifentrine Form I may have a powder X-ray diffraction pattern comprising at least five characteristic peaks selected from 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. Crystalline polymorph Form I typically has a differential scanning calorimetry trace exhibiting a maximum at 248°C.

[0040] The particles comprising the compound typically comprise at least 95% by weight or at least 99% by weight, based on the total weight of the particle, of ensifentrine crystalline polymorph Form I. The particles of the compound may consist essentially of ensifentrine crystalline polymorph Form I.

[0041] A liquid pharmaceutical composition typically comprises, by total weight of the liquid pharmaceutical composition: (i) ensifentrine particles at a concentration of 0.8 to 1.6 mg / mL, the ensifentrine particles having a Dv50 of about 1.0 μm to about 2.2 μm, and optionally a Dv10 of about 0.3 μm to about 0.9 μm and a Dv90 of about 2.3 μm to about 4.5 μm; (ii) one or more surfactants at a total concentration of 0.1 to 1.0 mg / mL; (iii) one or more buffers at a total concentration of 1.0 to 2.0 mg / ml; and (iv) water. Includes.

[0042] The liquid pharmaceutical composition may optionally further comprise (v) a tonicity adjuster at a concentration of 6.0 to 12.0 mg / mL. The tonicity adjuster is typically sodium chloride.

[0043] The liquid pharmaceutical composition may comprise, relative to the total weight of the liquid pharmaceutical composition: (i) ensifentrine particles at a concentration of 1.0 to 1.4 mg / mL, wherein the ensifentrine particles have a Dv50 of about 1.0 μm to about 2.2 μm, and optionally a Dv10 of about 0.3 μm to about 0.9 μm and a Dv90 of about 2.3 μm to about 4.5 μm; (ii) one or more surfactants at a total concentration of 0.4 to 0.7 mg / mL; (iii) one or more buffering agents at a total concentration of 1.4 to 1.8 mg / mL; (iv) water; and a tonicity adjuster at a concentration of 7.0 to 10.0 mg / mL.

[0044] The liquid pharmaceutical composition may comprise at least 95% by weight or at least 99% by weight of (i), (ii), (iii), (iv) and optionally (v), based on the total weight of the liquid pharmaceutical composition.

[0045] Examples of buffers include citrate buffers, phosphate buffers, acetate buffers, and bicarbonate buffers. Preferably, one or more buffers include a phosphate buffer, such as sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0046] Examples of surfactants are lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76, and Brij 97), polypropylene glycols (e.g., PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (polysorbates, e.g., 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, dodecyldimethylamine oxide, block copolymers of polyethylene glycol and polypropylene glycol (poloxamers), block copolymers of polyethylene glycol and polypropylene oxide (e.g., Pluronic surfactants), polyvinylpyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate, and polyethoxylated tallowamine (POEA).

[0047] Preferably, the one or more surfactants include polysorbate and / or sorbitan alkyl ester. The one or more surfactants may include, for example, polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). The one or more surfactants may include, for example, sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), or sorbitan trioleate (Span 85). Preferably, the one or more buffers include polysorbate 20 (Tween 20) and / or sorbitan monolaurate (Span 20).

[0048] The liquid pharmaceutical composition may comprise, relative to the total weight of the liquid pharmaceutical composition: (i) ensifentrine particles at a concentration of 1.0 to 1.4 mg / mL, the ensifentrine particles having a Dv10 of about 1.0 μm to about 2.2 μm, and optionally a Dv10 of about 0.3 μm to about 0.9 μm and a Dv90 of about 2.3 μm to about 4.5 μm; (ii) one or more surfactants at a total concentration of 0.4 to 0.7 mg / mL, the one or more surfactants being selected from polysorbates and / or sorbitan alkyl esters; (iii) one or more buffers at a total concentration of 1.4 to 1.8 mg / mL, the one or more buffers being selected from phosphate buffers; (iv) water; and sodium at a concentration of 7.0 to 10.0 mg / mL.

[0049] Ensifentrine particles are particles containing ensifentrine free base. Ensifentrine particles typically contain at least 90.0% by weight of ensifentrine, preferably at least 95.0% by weight. Ensifentrine particles can consist essentially of ensifentrine or can consist of ensifentrine. Ensifentrine particles typically contain at least 90.0% by weight or at least 95.0% by weight of ensifentrine crystalline polymorph Form I, as defined herein. For example, the ensifentrine particles may comprise at least 90% by weight of ensifentrine in the form of crystalline polymorph Form I having an X-ray powder diffraction pattern including at least five characteristic peaks selected from 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.

[0050] The liquid pharmaceutical composition may contain, based on the total weight of the liquid pharmaceutical composition: - ensifentrine particles at a concentration of 1.0 to 1.4 mg / mL, the ensifentrine particles having a Dv10 of about 0.3 μm to about 0.9 μm, a Dv50 of about 1.0 μm to about 2.2 μm, and a Dv90 of about 2.3 μm to about 4.5 μm; - Polysorbate 20 (Tween 20) at a concentration of 0.3 to 0.7 mg / mL; - sorbitan monolaurate (Span 20) in a concentration of 0.0 to 0.1 mg / mL; -Sodium dihydrogen phosphate dihydrate in a concentration of 0.5 to 1.0 mg / mL; - disodium hydrogen phosphate dihydrate in a concentration of 0.5 to 1.0 mg / mL; - sodium chloride in a concentration of 5 to 10 mg / mL; and - water and wherein the total weight of ensifentrine in the liquid pharmaceutical composition is 2.7 to 3.3 mg. The liquid pharmaceutical composition may comprise at least 95% by weight or at least 99% by weight of the listed ingredients, based on the total weight of the liquid pharmaceutical composition.

[0051] The liquid pharmaceutical composition may contain, based on the total weight of the liquid pharmaceutical composition: - ensifentrine particles at a concentration of 1.1 to 1.3 mg / mL, the ensifentrine particles having a Dv10 of 0.4 μm to 0.7 μm, a Dv50 of 1.2 μm to 1.9 μm, and a Dv90 of 2.9 μm to 4.3 μm; - Polysorbate 20 (Tween 20) at a concentration of 0.4 to 0.6 mg / mL; - sorbitan monolaurate (Span 20) in a concentration of 0.02 to 0.08 mg / mL; -Sodium dihydrogen phosphate dihydrate in a concentration of 0.65 to 0.85 mg / mL; - disodium hydrogen phosphate dihydrate in a concentration of 0.75 to 0.95 mg / mL; - sodium chloride in a concentration of 7 to 9 mg / mL; and - water and wherein the total weight of ensifentrine in the liquid pharmaceutical composition is 2.8 to 3.2 mg, and the ensifentrine particles comprise, based on the total weight of the ensifentrine particles, at least 95 wt% of ensifentrine crystalline polymorph Form I. The liquid pharmaceutical composition may comprise at least 95 wt% or at least 99 wt% of the listed ingredients, based on the total weight of the liquid pharmaceutical composition.

[0052] The liquid pharmaceutical composition may contain, based on the total weight of the liquid pharmaceutical composition: - ensifentrine particles at a concentration of about 1.2 mg / mL, the ensifentrine particles having a Dv10 of 0.4 μm to 0.7 μm, a Dv50 of 1.2 μm to 1.9 μm, and a Dv90 of 2.9 μm to 4.3 μm; - Polysorbate 20 (Tween 20) at a concentration of approximately 0.5 mg / mL; - sorbitan monolaurate (Span 20) at a concentration of approximately 0.05 mg / mL; - Sodium dihydrogen phosphate dihydrate at a concentration of approximately 0.74 mg / mL; - disodium hydrogen phosphate dihydrate at a concentration of approximately 0.85 mg / mL; sodium chloride at a concentration of about 8.6 mg / mL; and - water and Here, the total weight of ensifentrine in the liquid pharmaceutical composition is about 3.0 mg.

[0053] Typically, the total volume of the liquid pharmaceutical composition is 2.0 to 3.0 mL. For example, the total volume of the liquid pharmaceutical composition can be about 2.5 mL.

[0054] The present invention also provides a liquid pharmaceutical composition comprising: - ensifentrine particles at a concentration of 1.0 to 1.4 mg / mL, the ensifentrine particles having a Dv10 of about 0.3 μm to about 0.9 μm, a Dv50 of about 1.0 μm to about 2.2 μm, and a Dv90 of about 2.3 μm to about 4.5 μm; - Polysorbate 20 (Tween 20) at a concentration of 0.3 to 0.7 mg / mL; - sorbitan monolaurate (Span 20) in a concentration of 0.0 to 0.1 mg / mL; -Sodium dihydrogen phosphate dihydrate in a concentration of 0.5 to 1.0 mg / mL; - disodium hydrogen phosphate dihydrate in a concentration of 0.5 to 1.0 mg / mL; - sodium chloride in a concentration of 5 to 10 mg / mL; and - water and Herein, there is provided a liquid pharmaceutical composition, wherein the total weight of ensifentrine in the liquid pharmaceutical composition is 2.7 to 3.3 mg. The liquid pharmaceutical composition may be as further defined herein.

[0055] The ampoule typically contains 2.0 to 3.0 mL of the liquid pharmaceutical composition. The nebulizer contains the liquid pharmaceutical composition, and the liquid pharmaceutical composition is typically contained in the ampoule. The nebulizer can be a soft mist nebulizer, a vibrating mesh nebulizer, a jet nebulizer, or an ultrasonic nebulizer. The nebulizer is typically a jet nebulizer. The nebulizer can be, for example, a PARI LC Sprint jet nebulizer with a PARI Vios® PRO Aerosol Delivery System or a PARI BOY® compressor.

[0056] A method for treating COPD in a human subject comprises administering a liquid pharmaceutical composition to the human subject by inhalation. Typically, a therapeutically effective amount of the liquid pharmaceutical composition is administered to the human subject by inhalation.

[0057] COPD is typically moderate COPD or severe COPD. The stages of COPD can be classified as follows: FEV1 is forced expiratory volume in 1 second, and FVC is forced vital capacity. Mild COPD: FEV1 / FVC<0.7 and FEV1≥80% predicted Moderate COPD: FEV1 / FVC<0.7 and 50%≦FEV1<80% predicted Severe COPD: FEV1 / FVC<0.7 and 30%≦FEV1<50% predicted Most severe COPD: FEV1 / FVC<0.7 and FEV1<30% predicted

[0058] In each case, the actual FEV1 for a human subject is compared with the predicted FEV1 value based on factors such as the age and height of the human subject.These predicted values ​​can be easily obtained by those skilled in the art, 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 Crit Care. 1999; 159: 179-187).An example of the equation for calculating the predicted FEV1 (in L) for a human subject is as follows, where H is height (cm) and A is age (years): Male: 0.0430H-0.0290A-2.490 Women: 0.0395H-0.025A-2.600

[0059] FEV1 and FVC used to determine COPD severity in human subjects are measured by spirometry immediately after administration of an appropriate dose of at least one short-acting inhaled bronchodilator. Typically, FEV1 and FVC measurements for determining COPD disease severity are performed between 15 and 30 minutes following administration of salbutamol (albuterol).

[0060] Typically, FEV1 and FVC as used herein are determined as presented in the article Standardisation of spirometry, Eur J 2005; 26; 319-338.

[0061] A human subject may be determined to have moderate COPD by measuring FEV1 / FVC<0.7 and 50%≦FEV1<80% predicted FEV1 values, where FEV1 is forced expiratory volume in 1 second, and FVC is forced vital capacity measured between 15 and 30 minutes after administration of a bronchodilator, optionally wherein the bronchodilator is salbutamol. The patient's COPD severity may be determined at least one day before the first administration of the compound. A human subject may be determined to have severe COPD by measuring FEV1 / FVC<0.7 and 30%≦FEV1<50% predicted, where FEV1 is forced expiratory volume in 1 second, and FVC is forced vital capacity measured between 15 and 30 minutes after administration of a bronchodilator, optionally wherein the bronchodilator is salbutamol. The determination of the COPD severity in the human subject may be performed at least one day prior to the first administration of the compound.

[0062] The human subject may be male. The human subject may be female. The human subject may be 65 years of age or older. The human subject may be under 65 years of age. The human subject may be taking a background medication selected from one or more of a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA) and an inhaled corticosteroid (ICS). In some cases, the human subject is not taking a background medication. For example, the human subject may not be taking a background medication, and the background medication is a long-acting muscarinic antagonist (LAMA), a long-acting beta agonist (LABA) or an inhaled corticosteroid (ICS).

[0063] Preferably, the method comprises administering the compound to a human subject by inhalation from a nebulizer. The nebulizer aerosolizes the liquid pharmaceutical composition into an aerosol that is inhaled into the human subject's respiratory tract. Examples of nebulizers include soft mist nebulizers, vibrating mesh nebulizers, jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include Philips I-neb™ (Philips), Philips SideStream (Philips), AeroNeb® (Philips), Philips InnoSpire Go (Philips), Pari LC Sprint (Pari GmbH), AERxR™ Pulmonary Delivery System (Aradigm Corp), and Pari LC Plus Reusable Nebulizer (Pari GmbH). The nebulizer can be, for example, a PARI LC Sprint jet nebulizer with a PARI Vios® PRO Aerosol Delivery System PARI BOY® compressor. The compound may be inhaled via a nebulizer for 1 to 15 minutes, such as 5 to 10 minutes, or approximately 7 minutes.

[0064] Typically, the method comprises administering the compound to a human subject once, twice or three times a day, for example, twice or three times a day.The compound can be administered to a human subject by inhalation once, twice or three times a day.Preferably, the method comprises administering the compound to a human subject by inhalation twice a day.The method can comprise administering a first dose of the compound in the morning (for example, within 3 hours after waking up) and a second dose of the compound in the evening (for example, within 3 hours before going to bed).Typically, the morning and evening doses are administered 10 to 14 hours apart, for example, about 12 hours apart.

[0065] Typically, the compound is administered twice daily in two separate doses that are the same or similar. Typically, the method can include administering the compound to a human subject twice daily in a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

[0066] Preferably, the method comprises administering two doses of a liquid pharmaceutical composition containing about 3 mg of ensifentrine free base to a human subject by inhalation per day. Preferably, the method comprises administering about 3 mg of the compound twice daily (3 mg BID) to a human subject by inhalation. More preferably, the method comprises administering about 3 mg of the compound twice daily to a human subject by nebulizer. Each dose can be 3.0 mg of ensifentrine free base administered by nebulizer.

[0067] The compound is typically used as maintenance therapy.Typically, the method comprises administering the compound to human subjects at least once a day for at least 8 weeks.The compound can be administered to human subjects at least once a day for at least 16 weeks, preferably at least 24 weeks.The compound can be administered to human subjects every day for at least 1 year.The method can comprise administering the compound to human subjects at least once every 24 hours, preferably at least twice every 24 hours, for at least 8 weeks, preferably at least 16 weeks, more preferably at least 24 weeks.

[0068] Administering the liquid pharmaceutical composition to a human subject by inhalation provides a plasma concentration of ensifentrine having a mean C of about 400 pg / mL to about 720 pg / mL. max and / or approximately 2000 pg / mL * h to approximately 3000 pg / mL * Mean AUC of h 0-tau and / or a mean T of about 0.8 hours to about 1.3 hours max The mean pharmacokinetic profile (or the pharmacokinetic profile achieved in an individual human subject) may be as further defined above for the liquid pharmaceutical composition.

[0069] Administration of the liquid pharmaceutical composition by inhalation to a human subject typically provides a mean increase in baseline FEV1 of at least 20 mL.

[0070] The present invention also provides a liquid pharmaceutical composition as defined herein for use in a method of treating COPD as defined herein. Further provided is the use of a liquid pharmaceutical composition as defined herein in the manufacture of a medicament for use in a method of treating COPD as defined herein.

[0071] The invention will now be described in further detail by the following examples. [Example]

[0072] Study design A clinical study was conducted to determine the efficacy of ensifentrine compared with placebo in treating COPD. Ensifentrine was administered via nebulizer at a dose of 3 mg twice daily (BID) for 24 weeks. The study was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial with approximately 800 patients and a 5:3 randomization.

[0073] The study population included patients aged 40–80 years with moderate to severe COPD (mMRC ≥ 2, FEV1 30–70% pn, FEV1 / forced vital capacity (FVC) ratio < 0.7). Randomization was stratified by (a) stable background maintenance LAMA or LABA therapy use (approximately 50%; yes or no) and (b) cigarette smoking (current or former). Inhaled corticosteroid (ICS) maintenance therapy was permitted in up to 20% of patients under certain conditions.

[0074] The primary endpoint of the study was the change from baseline in mean FEV1 area under the curve (AUC) 0-12 hours post-dose at week 12. Secondary endpoints of the study included: peak FEV1 over 4 hours post-dose at week 12; morning nadir FEV1 at week 12; and other endpoints, including the frequency of moderate / severe COPD exacerbations over 24 weeks.

[0075] method Baseline FEV1 is the average of two measurements taken before study drug on the day of first dosing, i.e., within 40 minutes, and immediately before dosing on Day 1, both taken pre-dose.

[0076] Mean FEV1AUC0-12h is defined as the area under the curve of FEV1 over 12 hours divided by 12 hours.

[0077] Plasma concentrations of ensifentrine for evaluation of pharmacokinetic (PK) parameters were measured using a validated bioanalytical method for ensifentrine in human plasma, with an LLOQ of 5 pg / mL.

[0078] Samples were taken on the following schedule: Week 6: 1.0 hour (±0.5 hour) and 2.5 hours (±0.5 hour) (even sites) or 1.5 hours and 4 hours (±1 hour) (odd sites); Week 12: Pre-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: Pre-dose (-0.5 hours) and 1.5 hours (even-numbered sites) or pre-dose (-0.5 hours) and 1 hour (±0.5 hours) (odd-numbered sites)

[0079] formulation The study drug and placebo were provided in a 2.5 mL unit dose format in ampoules and administered via a nebulizer. The formulations of the study drug (ensifentrine suspension formulation containing crystalline polymorphic Form I of ensifentrine) and placebo are shown in Table 1 below.

[0080] [Table 1]

[0081] result The primary endpoint of mean FEV1 (AUC) 0-12h at 12 weeks was met. All subgroups showed statistically significant improvements in lung function with ensifentrine. Results are shown in Table 2.

[0082] [Table 2]

[0083] Based on samples acquired during the study, PK data were modeled for COPD patients with normal renal function. The final popPK model was used to predict parameter estimates in a hypothetical population of 50,000 subjects (per covariate condition) for simulation of ensifentrine PK following 3 mg nebulization in populations reflecting the study population with normal renal function, mild renal impairment, or moderate renal impairment. Uncertainty in the fixed effects and covariance matrix parameters, as well as residual variation, were included in the simulation. Parameter uncertainty was accounted for by random resampling (without replacement) of 500 sets of parameter estimates from bootstrapping (750 replicates) in R to generate 500 NONMEM simulation control streams. From each set of parameter estimates, PK profiles for 100 subjects (for each covariate 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 PK parameters were calculated using R version 3.4.0.

[0084] The results are shown in Table 3.

[0085] [Table 3]

[0086] conclusion Ensifentrine was found to provide statistically significant improvements in lung function in all subgroups of COPD patients in the study.

[0087] Mean C of 522 pg / mL max and 2450 pg / mL * Mean AUCs of 0.05 h were achieved in patients with COPD. These values ​​are comparable to the mean C values ​​observed following administration of the composition to healthy patients. max (852 pg / mL) and mean AUC (5929 pg / mL * Mean AUC of h 0-∞ ) lower, indicating lower systemic exposure of ensifentrine in COPD patients than in healthy patients.

Claims

1. A liquid pharmaceutical composition comprising a dose of a compound which is ensifentrin or a pharmaceutically acceptable salt thereof, Here, the liquid pharmaceutical composition provides a plasma concentration of ensifentrin after administration by inhalation to a human subject having COPD, and the plasma concentration of ensifentrin is: Average C levels ranging from approximately 400 pg / mL to approximately 720 pg / mL ｍａｘ ; and / or Approximately 2000pg / mL ＊ From h to approximately 3000 pg / mL ＊ Average AUC of h ０－ｔａｕ ; and / or Average T of approximately 0.6 to 1.5 hours ｍａｘ A liquid pharmaceutical composition having [a certain characteristic].

2. After administration of the liquid pharmaceutical composition by inhalation to human subjects with COPD, the average C1c level ranged from approximately 400 pg / mL to approximately 720 pg / mL. ｍａｘ The liquid pharmaceutical composition according to claim 1, which provides a plasma concentration of ensifentrin having the properties of ensifentrin.

3. The average C ｍａｘ The liquid pharmaceutical composition according to claim 2, wherein the concentration is approximately 500 pg / mL to approximately 600 pg / mL.

4. The liquid pharmaceutical composition provides a plasma concentration of ensifentrine having an average AUC of about 2000 pg / mL ＊ from about h to about 3000 pg / mL ＊ h ０－ｔａｕ after administration by inhalation to a human subject having COPD, the liquid pharmaceutical composition according to claim 1.

5. The average AUC ０－ｔａｕ Approximately 2300 pg / mL ＊ From h to approximately 2600 pg / mL ＊ The liquid pharmaceutical composition according to claim 4, wherein h is present.

6. The liquid pharmaceutical composition, after inhalation by a human subject with COPD, shows an average T145 (T145) of approximately 0.6 to 1.5 hours. ｍａｘ The liquid pharmaceutical composition according to claim 1, which provides a plasma concentration of ensifentrin having the properties of ensifentrin.

7. The average T ｍａｘ The liquid pharmaceutical composition according to claim 6, wherein the incubation period is approximately 0.8 hours to approximately 1.3 hours.

8. The liquid pharmaceutical composition provides a plasma concentration of ensifentrin after administration by inhalation to a human subject having COPD, wherein the plasma concentration of ensifentrin is: Average C levels ranging from approximately 500 pg / mL to approximately 600 pg / mL ｍａｘ ; and Approximately 2350pg / mL ＊ From h to approximately 2550 pg / mL ＊ Average AUC of h ０－ｔａｕ ; and Average T of approximately 0.8 hours to approximately 1.3 hours ｍａｘ A liquid pharmaceutical composition according to claim 1, comprising the features described above.

9. The average C ｍａｘ , the average AUC ０－ｔａｕ and the average T ｍａｘ However, after administration of the liquid pharmaceutical composition, the plasma concentration in a sample of a human subject with COPD is measured by determining the concentration at regular intervals. The liquid pharmaceutical composition according to claim 1, wherein optionally, the interval is two or more of 1.0 hours (±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.

10. The liquid pharmaceutical composition according to claim 9, wherein the plasma concentration is determined using an analytical method having an LLOQ of about 5.0 pg / mL or less.

11. The liquid pharmaceutical composition according to claim 1, wherein the dose of the compound is approximately 2.5 mg to approximately 3.5 mg.

12. The liquid pharmaceutical composition according to claim 1, wherein the dose of the compound is approximately 3.0 mg.

13. The liquid pharmaceutical composition, after administration by inhalation to a human subject, reaches a baseline FEV of at least 20 mL. １ The liquid pharmaceutical composition according to claim 1, which provides an average increase in [location].

14. The liquid pharmaceutical composition according to claim 1, wherein the liquid pharmaceutical composition comprises (a) a suspension of particles containing the compound and (b) a diluent.

15. The liquid pharmaceutical composition according to claim 14, wherein the particles containing the compound have a Dv50 of about 0.2 μm to about 5.0 μm.

16. The liquid pharmaceutical composition according to claim 14, wherein the particles containing the compound have a Dv50 of about 1.0 μm to about 2.2 μm.

17. The liquid pharmaceutical composition according to claim 14, wherein the particles containing the compound have a Dv10 of about 0.3 μm to about 0.9 μm and / or a Dv90 of about 2.3 μm to about 4.5 μm.

18. The liquid pharmaceutical composition according to claim 14, wherein the particles containing the compound are particles containing at least 95% by weight of ensifentrin.

19. The liquid pharmaceutical composition, in relation to the total weight of the liquid pharmaceutical composition: (i) Encifentrin particles having a concentration of 0.8 to 1.6 mg / mL, wherein the encifentrin particles have a Dv50 of about 1.0 μm to about 2.2 μm, and optionally a Dv10 of about 0.3 μm to about 0.9 μm and a Dv90 of about 2.3 μm to about 4.5 μm; (ii) One or more surfactants in a total concentration of 0.1 to 1.0 mg / mL; (iii) One or more buffers for a total concentration of 1.0 to 2.0 mg / ml; and (iv) Water A liquid pharmaceutical composition according to claim 1, comprising:

20. The liquid pharmaceutical composition, in relation to the total weight of the liquid pharmaceutical composition: - Encifentrin particles having a concentration of 1.0 to 1.4 mg / mL, wherein the encifentrin particles have a Dv10 of about 0.3 μm to about 0.9 μm, a Dv50 of about 1.0 μm to about 2.2 μm, and a Dv90 of about 2.3 μm to about 4.5 μm; - Polysorbate 20 (Tween 20) at concentrations of 0.3 to 0.7 mg / mL; - Sorbitan monolaurate (Span 20) at concentrations of 0.0 to 0.1 mg / mL; - Sodium dihydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg / mL; - Disodium hydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg / mL; - Sodium chloride in concentrations of 5 to 10 mg / mL; and - water Including, and The liquid pharmaceutical composition according to claim 1, wherein the total weight of ensifentrin in the liquid pharmaceutical composition is 2.7 to 3.3 mg.

21. The liquid pharmaceutical composition, in relation to the total weight of the liquid pharmaceutical composition: - Encifentrin particles having a concentration of approximately 1.2 mg / mL, wherein the encifentrin particles have a Dv10 of 0.4 μm to 0.7 μm, a Dv50 of 1.2 μm to 1.9 μm, and a Dv90 of 2.9 μm to approximately 4.3 μm; - Polysorbate 20 (Tween 20) at a concentration of approximately 0.5 mg / mL; - Sorbitan monolaurate (Span 20) at a concentration of approximately 0.05 mg / mL; - Sodium dihydrogen phosphate dihydrate at a concentration of approximately 0.744 mg / mL; - Disodium hydrogen phosphate dihydrate at a concentration of approximately 0.853 mg / mL; - Sodium chloride at a concentration of approximately 8.6 mg / mL; and - water Including, and The liquid pharmaceutical composition according to claim 1, wherein the total weight of ensifentrin in the liquid pharmaceutical composition is about 3.0 mg.

22. The liquid pharmaceutical composition according to claim 19, wherein the ensifentrin particles comprise ensifentrin in the form of crystalline polymorph I having a powder X-ray diffraction pattern including at least 90% by weight of ensifentrin having a powder X-ray diffraction pattern including at least five characteristic peaks selected from 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.

23. The liquid pharmaceutical composition according to claim 1, wherein the total volume of the liquid pharmaceutical composition is 2.0 to 3.0 mL, preferably, the total volume of the liquid pharmaceutical composition is about 2.5 mL.

24. The liquid pharmaceutical composition according to claim 1, wherein the human subject has moderate or severe COPD.

25. An ampoule comprising the liquid pharmaceutical composition as defined in Claim 1.

26. A nebulizer comprising the liquid pharmaceutical composition as defined in claim 1.

27. A method for the manufacture of a pharmaceutical for a method of treating COPD in a human subject, comprising the use of a liquid pharmaceutical composition as defined in claim 1, wherein the method includes administering the liquid pharmaceutical composition as defined in any one of claims 1 to 24 to the human subject by inhalation.

28. The use according to claim 27, wherein the COPD is moderate or severe COPD.

29. Administering the liquid pharmaceutical composition to a human subject by inhalation provides a plasma concentration of ensifentrin, and the plasma concentration of ensifentrin is: Average C levels ranging from approximately 400 pg / mL to approximately 720 pg / mL ｍａｘ ; and / or Approximately 2000pg / mL ＊ From h to approximately 3000 pg / mL ＊ Average AUC of h ０－ｔａｕ ; and / or Average T of approximately 0.8 hours to approximately 1.3 hours ｍａｘ The use according to claim 27, having the following characteristics.

30. The use according to claim 27, wherein administering the liquid pharmaceutical composition to a human subject by inhalation provides an average increase in baseline FEV1 of at least 20 mL.