Liquid pharmaceutical composition

Abstract

The present invention is directed to a liquid pharmaceutical composition comprising a dose of a compound that is ensafenetine or a pharmaceutically acceptable salt thereof wherein the liquid pharmaceutical composition provides a plasma concentration of ensafenetine upon administration by inhalation to a human individual suffering from COPD, the plasma concentration of ensafenetine having: an average Cmax of from about 400 pg / mL to about 720 pg / mL; and / or an average AUC0-tau of from about 2000 pg / mL * h to about 3000 pg / mL * h; and / or an average Tmax of from about 0.6 hours to about 1.5 hours. The invention also provides a method of treating COPD.

Description

Field of the Invention

[0001] The present invention relates to a liquid pharmaceutical composition comprising a dose of a compound, which is encefantine or a pharmaceutically acceptable salt thereof. Background of the Invention

[0003] Ensefentin (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 WO00 / 58308A1.

[0004] As a combined PDE3 / PDE4 inhibitor, Enseifentin has bronchodilatory and anti-inflammatory activities and is useful for treating respiratory diseases including chronic obstructive pulmonary disease (COPD). The chemical structure of Enseifentin is shown below.

[0005]

[0006] COPD is a progressive, long-term disease. Enseifentine is usually administered to COPD patients by nebulizer as a maintenance therapy. It would be beneficial to provide an enseifentine plasma concentration with a desired pharmacokinetic profile in COPD patients after inhalation of a liquid pharmaceutical composition suitable for inhalation. SUMMARY OF THE INVENTION

[0008] It has been found that a liquid pharmaceutical composition comprising a dose of encefantine or a pharmaceutically acceptable salt thereof is capable of providing a favorable plasma concentration of encefantine following inhalation into a human subject suffering from COPD.

[0009] Thus, the present invention provides a liquid pharmaceutical composition comprising a dose of a compound, which is Enseifantine or a pharmaceutically acceptable salt thereof, wherein the liquid pharmaceutical composition provides a plasma concentration of Enseifantine after administration by inhalation to a human subject suffering from COPD, wherein the plasma concentration of Enseifantine has:

[0010] Average C from about 400 pg / mL to about 720 pg / mL max ; and / or

[0011] Average AUC from about 2000 pg / mL*h to about 3000 pg / mL*h 0-tau ; and / or

[0012] Average T of about 0.6 hours to about 1.5 hours max .

[0013] The present invention also provides an ampoule containing the liquid drug composition. The present invention also provides a nebulizer containing the liquid drug composition.

[0014] The present invention also provides a method of treating COPD in a human subject, the method comprising administering to the human subject a liquid pharmaceutical composition by inhalation. DETAILED DESCRIPTION OF THE INVENTION

[0016] The liquid pharmaceutical composition provides a plasma concentration of encefantine after administration by inhalation to a human subject suffering from COPD, the plasma concentration of encefantine having a mean C of about 400 pg / mL to about 720 pg / mL. max and / or a mean AUC of about 2000 pg / mL*h to about 3000 pg / mL*h 0-tau and / or an average T of about 0.6 hours to about 1.5 hours max Thus, the liquid pharmaceutical composition is suitable for providing a plasma concentration of encefantine following administration by inhalation to a human subject suffering from COPD, for example following administration by inhalation from a nebulizer.

[0017] C max , AUC 0-tau and T max It is a pharmacokinetic parameter well known to those skilled in the art. max is the maximum concentration of a compound in plasma achieved after administration of the compound. max It is observed that C max AUC is the area under the curve of the plasma concentration of a compound as a function of time after administration over a given period of time. 0-tau It is the AUC from dosing to the end of the dosing period (which can be, for example, 8 hours, 12 hours, or 24 hours). As used herein, tau is generally 12 hours and AUC 0-tau AUC 0-12h .

[0018] Typically, a liquid pharmaceutical composition provides a mean C of about 400 pg / mL to about 720 pg / mL after administration by inhalation to a human subject with COPD. max The mean plasma concentration of ensefentin was max It can be about 500 μg / mL to about 600 μg / mL. For example, the average C max It may be about 500 pg / mL to about 550 pg / mL, or about 520 pg / mL to about 525 pg / mL.

[0019] Typically, the liquid pharmaceutical composition provides a mean AUC of about 2000 pg / mL*h to about 3000 pg / mL*h after administration by inhalation to a human subject with COPD.0-tau The mean AUC of ensefentin was 0-tau It can be from about 2300 pg / mL*h to about 2600 pg / mL*h. For example, the average AUC 0-tau It may be about 2400 pg / mL*h to about 2500 pg / mL*h, or about 2425 pg / mL*h to about 2475 pg / mL*h.

[0020] The liquid pharmaceutical composition may provide a mean C of about 400 pg / mL to about 720 pg / mL after administration by inhalation to a human subject suffering from COPD. max and an average AUC of about 2000 pg / mL*h to about 3000 pg / mL*h 0-tau plasma concentration.

[0021] Typically, the liquid pharmaceutical composition provides a mean T of about 0.6 hours to about 1.5 hours after administration by inhalation to a human subject with COPD. max The mean plasma concentration of ensefentin was max It can be from about 0.8 hours to about 1.3 hours. For example, the average T max It may be from about 0.9 hours to about 1.1 hours, from about 0.95 hours to about 1.05 hours.

[0022] The liquid pharmaceutical composition can provide a plasma concentration of encefantine after administration by inhalation to a human subject suffering from COPD, the plasma concentration of encefantine having a mean C of about 500 pg / mL to about 600 pg / mL. max ; and a mean AUC of about 2300 pg / mL*h to about 2600 pg / mL*h 0-tau and an average T of about 0.8 hours to about 1.3 hours max The plasma concentration of Ensefentin may have a mean C of about 510 pg / mL to about 530 pg / mL. max and a mean AUC of about 2350 pg / mL*h to about 3550 pg / mL*h 0-tau and an average T of about 0.9 hours to about 1.1 hours max .

[0023] As used herein, the term "about" may mean a variation of ±10% of the stated value.

[0024] The average plasma concentration profile provided in human subjects with COPD can be determined based on the average plasma concentration of ensefantin observed after administration of a sample liquid pharmaceutical composition by inhalation to human subjects with COPD. Typically, the average C max , average AUC 0-tauand average T max It is measured by measuring the plasma concentration in a sample of human subjects suffering from COPD at intervals after administration of the liquid pharmaceutical composition. The sample of human subjects may include 100 to 1000 human subjects, such as 300 human subjects. The human subjects in the sample may have an age of 45 to 75 years old.

[0025] Those skilled in the art will appreciate the appropriate time intervals for measuring the plasma concentration after inhalation of a liquid pharmaceutical composition. Typically, the interval is two or more -0.5h (±0.5h, i.e., before administration), 0.5h (±0.25h), 1.0h (±0.5h), 1.5h (±0.5h), 2.0h (±0.5h), 2.5h (±0.5h), 3.0h (±0.5h), 4.0h (±1h), 6.0h (±1h), 8.0h (±1h), 10.0h (±1h), 12.0h (±1h), 24.0h (±1h), 36.0h (±1h), 48.0h (±1h), 56.0h (±1h), and 60.0h (±1h) after administering the liquid pharmaceutical composition. The interval can be two or more 1.0h (± 0.5h), 2.0h (± 0.5h), 3.0h (± 0.5h), 4.0h (± 1h), 12.0h (± 1h), 24.0h (± 1h), 36.0h (± 1h), 48.0h (± 1h) and 56.0h (± 1h) after administration of the liquid pharmaceutical composition. For example, the interval can be -0.5h (± 0.5h, i.e. before administration), 0.5h (± 0.25h), 1.0h (± 0.5h), 2.0h (± 0.5h), 3.0h (± 0.5h), 4.0h (± 1h) and 12.0h (± 1h).

[0026] Typically, plasma concentrations are determined using an analytical method with a LLOQ of no greater than about 5.0 pg / mL.

[0027] Administration of a liquid pharmaceutical composition to a human subject by inhalation generally comprises 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, which 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), (Philips), Philips InnoSpire Go (Philips), Pari LC sprint (Pari GmbH), AERxRTM pulmonary delivery system (Aradigm Corp) and Pari LC Plus reusable nebulizer (Pari GmbH). The nebulizer can be, for example, a PARI PRO Aerosol Delivery System PARI PARI LC Sprint jet nebulizer with compressor. The liquid drug composition can be inhaled through the nebulizer for 1 to 15 minutes, such as 5 to 10 minutes.

[0028] For example, the average C max , average AUC 0-tau and average T max It can be measured by determining the average plasma concentration in a sample of 300 human subjects with COPD at intervals after administration of the liquid pharmaceutical composition, wherein the human subjects in the sample may have an age of 45 to 75 years old, and wherein the liquid pharmaceutical composition may be inhaled via a nebulizer for 1 to 15 minutes (e.g., about 7 minutes). The human subject may have moderate COPD.

[0029] The human subject typically receives the compound as a maintenance therapy. The compound can be administered to the human subject once, twice, or three times daily. The compound is preferably administered as a twice daily maintenance therapy.

[0030] The liquid pharmaceutical composition comprises a dose of a compound, which is ensefentin or a pharmaceutically acceptable salt thereof. Typically, the dose is about 2 mg to about 4 mg of the compound. For example, the dose may be 2.5 mg to 3.5 mg of the compound. The dose may 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.

[0031] The dosage may be 2.8 mg to 3.2 mg of enseifentine (ie, enseifentine free base). The dosage is typically about 3 mg of enseifentine, for example 3.0 mg of enseifentine.

[0032] The concentration of the compound in the liquid pharmaceutical composition is generally 0.8 to 1.6 mg / mL. For example, the liquid pharmaceutical composition generally contains 1.0 to 1.4 mg / mL of ensefentin. The liquid pharmaceutical composition may contain 1.1 to 1.3 mg / mL of ensefentin. The liquid pharmaceutical composition may contain about 1.2 mg / mL of ensefentin.

[0033] Inhalation of liquid pharmaceutical compositions generally only includes a portion of inhaled liquid pharmaceutical compositions. Therefore, for example, due to the remaining liquid pharmaceutical composition being retained in the nebulizer for delivering the liquid pharmaceutical composition by inhalation, only a portion of the liquid pharmaceutical composition is generally delivered to the patient. The portion of the liquid pharmaceutical composition delivered from the nebulizer to the patient's lungs can be 20 to 40% volume ratio of the liquid pharmaceutical composition initially present in the nebulizer before administration. The portion of the liquid pharmaceutical composition delivered from the nebulizer to the patient's lungs can be 25 to 35% volume ratio of the liquid pharmaceutical composition initially present in the nebulizer before administration, such as 29 to 33% volume ratio or about 31% volume ratio. Therefore, the average delivery dose of the compound inhaled by human individuals is generally 20% to 40%, 25% to 35% or 29% to 33% of the total dose present in the liquid pharmaceutical composition before administration. When using a nebulizer for administration, the average delivery dose of the compound (for example, the average delivery dose of Ensefentin free base) is generally 0.7 to 1.1 mg. The average delivery dose can be 0.8 to 1.0 mg, such as 0.90 to 0.95 mg. The nebulizer is typically a jet nebulizer. The liquid pharmaceutical composition is typically suitable for providing a mean C defined herein after delivery from the nebulizer as described above. max , average AUC 0-tau and average T max .

[0034] The invention also provides a liquid pharmaceutical composition as defined herein, which provides an average delivered dose of 0.7 to 1.1 mg of the compound when administered using a nebulizer. The average delivered dose may be 0.8 to 1.0 mg, such as 0.90 to 0.95 mg.

[0035] The liquid pharmaceutical composition generally provides an average increase of at least 20 mL of baseline FEV1 after administration to a human subject by inhalation. For example, the liquid pharmaceutical composition can provide an average increase of at least 30 mL of baseline FEV1 after administration to a human subject by inhalation. Typically, as used herein, FEV1 is measured as described in Standardisation of Spirometry Eur J 2005; 26; 319-338.

[0036] Liquid pharmaceutical compositions typically comprise (a) a suspension of particles comprising a compound and (b) a diluent. The diluent is typically water. In the case where some or all of the particles comprising the compound in the liquid pharmaceutical composition have settled to the bottom of a container containing the liquid pharmaceutical composition, for example after a period of storage. The particles comprising the compound may be resuspended in any suitable manner, for example by stirring the sterile liquid pharmaceutical composition.

[0037] The particles comprising the compound typically have a Dv50 of about 0.2 μm to about 5.0 μm. For example, the particles comprising 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.

[0038] Particle size is described herein by reference to the Dv50 value, which is the median particle size of the volume distribution. Thus, half of the volume of particles have a diameter smaller than the Dv50 value, and half of the volume of particles have a diameter larger than the Dv50 value. This is a well-known way of describing particle size distribution. The parameters Dv10 and Dv90 can also be used to characterize the particle size distribution of a sample. 10% of the volume of particles have a diameter smaller than the Dv10 value. 90% of the volume of particles have a diameter smaller than the Dv90 value.

[0039] 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.

[0040] 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.

[0041] The technique used to measure Dv10, Dv50 and Dv90 values ​​as described herein is generally laser diffraction. The particle size distribution of particles comprising the compound can be measured by laser diffraction using a wet powder dispersion system. For example, the particle size distribution can be measured using the laser diffraction of a Malvern Spraytec in conjunction with a wet dispersion cell. Typically, the instrument parameters of the Malvern Spraytec are as follows:

[0042] · Grains – standard opaque granules;

[0043] Refractive index particles -1.50;

[0044] Refractive index (imaginary part) -0.50;

[0045] Particle density - 1.00;

[0046] The refractive index of the dispersant is -1.33;

[0047] Controller unit - 1000RPM;

[0048] Measurement type – timing;

[0049] Initial sampling time - 30s;

[0050] · Shading - 20% to 30%;

[0051] Dispersant - 1% polysorbate 20 in deionized water.

[0052] The encefantine particles may be produced by any pharmaceutically acceptable size reduction method or particle size control production method. For example, the particles may be prepared by spray drying an encefantine solution, by controlled crystallization, or by size reduction of encefantine in solid form, such as by air jet milling, mechanical micronization or media milling.

[0053] The particles comprising the compound generally comprise ensephentin (i.e., ensephentin free base). The particles comprising the compound may comprise at least 90% by weight of ensephentin free base relative to the total weight of the particles, such as at least 95% by weight of ensephentin. The particles may comprise at least 99% by weight of ensephentin. The particles may consist of ensephentin.

[0054] The compound is generally in crystalline form. The particles containing the compound generally contain at least 90% by weight of ensefentin free base form I relative to the total weight of the particles. Ensefentin free base form I is a crystalline polymorph of ensefentin (crystalline polymorph form I), which generally has a powder X-ray diffraction pattern comprising characteristic peaks at 10.1° and 12.9°±0.1°2θ. As described herein, the value of °2θ is generally determined using the X-ray wavelength of CuKα radiation. Measured. The powder X-ray diffraction pattern of Form I generally also includes characteristic peaks at 15.3° and 17.6°±0.1°2θ. Form I of Ensefentin may have a powder X-ray diffraction pattern comprising at least 5 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. The crystalline polymorph Form I generally has a differential scanning calorimetry trace showing a maximum at 248°C.

[0055] The particles comprising the compound typically comprise at least 95% by weight or at least 99% by weight of crystalline polymorph Form I of encefantine relative to the total weight of the particles. The particles of the compound may consist essentially of crystalline polymorph Form I of encefantine.

[0056] Relative to the total weight of the liquid pharmaceutical composition, the liquid pharmaceutical composition generally comprises:

[0057] (i) Ensephentin particles at a concentration of 0.8 to 1.6 mg / mL, the Ensephentin particles having a Dv50 of about 1.0 μm to about 2.2 μm, and optionally having 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;

[0058] (ii) one or more surfactants at a total concentration of 0.1 to 1.0 mg / mL;

[0059] (iii) one or more buffers at a total concentration of 1.0 to 2.0 mg / ml; and (iv) water.

[0060] 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.

[0061] Relative to the total weight of the liquid pharmaceutical composition, the liquid pharmaceutical composition may comprise: (i) Ensefentin particles at a concentration of 1.0 to 1.4 mg / mL, wherein the Ensefentin particles have a Dv50 of about 1.0 μm to about 2.2 μm, and optionally have 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, whose total concentration is 0.4 to 0.7 mg / mL; (iii) one or more buffers, whose total concentration is 1.4 to 1.8 mg / ml; (iv) water; and a tonicity regulator, whose concentration is 7.0 to 10.0 mg / mL.

[0062] 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), relative to the total weight of the liquid pharmaceutical composition.

[0063] Examples of buffers include citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer.Preferably, the one or more buffers comprise a phosphate buffer, such as sodium dihydrogen phosphate dihydrate and / or disodium phosphate dihydrate.

[0064] Examples of surfactants include lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76, and Brij 97), polypropylene glycol (e.g., PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80), sorbitan alkyl esters (e.g., sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), and sorbitan trioleate (Span 100). 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), polyvinyl pyrrolidone K25, polyvinyl alcohol, oligomeric lactic acid, sodium dioctyl sulfosuccinate and polyethoxylated tallow amine (POEA).

[0065] Preferably, the one or more surfactants include polysorbates and / or sorbitan alkyl esters. The one or more surfactants may, for example, include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). The one or more surfactants may, for example, include 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).

[0066] Relative to the total weight of the liquid pharmaceutical composition, the liquid pharmaceutical composition may comprise: (i) an ensefentin particle at a concentration of 1.0 to 1.4 mg / mL, the ensefentin particle having a Dv50 of about 1.0 μm to about 2.2 μm, and optionally having 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, whose total concentration is 0.4 to 0.7 mg / mL, which are selected from polysorbates and / or sorbitan alkyl esters; (iii) one or more buffers, whose total concentration is 1.4 to 1.8 mg / mL, which are selected from phosphate buffer; (iv) water; and sodium at a concentration of 7.0 to 10.0 mg / mL.

[0067] The ensephentin particles are particles comprising ensephentin free base. The ensephentin particles generally contain at least 90.0% by weight of ensephentin, preferably at least 95.0% by weight. The ensephentin particles may be substantially composed of ensephentin, or may be composed of ensephentin. The ensephentin particles generally contain at least 90.0% by weight or at least 95.0% by weight of ensephentin crystalline polymorph Form I as defined herein. For example, the ensefentin particles may contain at least 90% by weight of ensefentin crystalline polymorph Form I, having a powder X-ray diffraction pattern comprising at least 5 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.

[0068] Relative to the total weight of the liquid pharmaceutical composition, the liquid pharmaceutical composition may comprise:

[0069] - Ensephentin particles at a concentration of 1.0 to 1.4 mg / mL, the Ensephentin particles having a Dv10 of about 0.3 to 0.9 μm, a Dv50 of about 1.0 to 2.2 μm, and a Dv90 of about 2.3 to 4.5 μm;

[0070] - Polysorbate 20 (Tween 20) at a concentration of 0.3 to 0.7 mg / mL;

[0071] - Sorbitan monolaurate (Span 20) at a concentration of 0.0 to 0.1 mg / mL;

[0072] - sodium dihydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg / mL;

[0073] - disodium hydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg / mL;

[0074] - sodium chloride at a concentration of 5 to 10 mg / mL; and

[0075] - Water, and

[0076] The total weight of Ensefentin in the liquid pharmaceutical composition is 2.7 to 3.3 mg. The liquid pharmaceutical composition may contain at least 95% by weight or at least 99% by weight of the listed components relative to the total weight of the liquid pharmaceutical composition.

[0077] Relative to the total weight of the liquid pharmaceutical composition, the liquid pharmaceutical composition may comprise:

[0078] - Ensephentin particles at a concentration of 1.1-1.3 mg / mL, the Ensephentin particles having a Dv10 of 0.4-0.7 μm, a Dv50 of 1.2 to 1.9 μm, and a Dv90 of 2.9 to 4.3 μm;

[0079] - Polysorbate 20 (Tween 20) at a concentration of 0.4 to 0.6 mg / mL;

[0080] - Sorbitan monolaurate (Span 20) at a concentration of 0.02 to 0.08 mg / mL;

[0081] - sodium dihydrogen phosphate dihydrate at a concentration of 0.65 to 0.85 mg / mL;

[0082] - disodium hydrogen phosphate dihydrate at a concentration of 0.75 to 0.95 mg / mL;

[0083] - sodium chloride at a concentration of 7 to 9 mg / mL; and

[0084] - Water, and

[0085] wherein the total weight of encefantine in the liquid pharmaceutical composition is 2.8 to 3.2 mg, and wherein the encefantine particles contain at least 95% by weight of encefantine crystalline polymorph Form I relative to the total weight of the encefantine particles. The liquid pharmaceutical composition may contain at least 95% by weight or at least 99% by weight of the listed components relative to the total weight of the liquid pharmaceutical composition.

[0086] Relative to the total weight of the liquid pharmaceutical composition, the liquid pharmaceutical composition may comprise:

[0087] - Ensefentin particles at a concentration of about 1.2 mg / mL, the Ensefentin particles having a Dv10 of 0.4 to 0.7 μm, a Dv50 of 1.2 to 1.9 μm, and a Dv90 of 2.9 to 4.3 μm;

[0088] - Polysorbate 20 (Tween 20) at a concentration of about 0.5 mg / mL;

[0089] - Sorbitan monolaurate (Span 20) at a concentration of about 0.05 mg / mL;

[0090] - sodium dihydrogen phosphate dihydrate at a concentration of about 0.74 mg / mL;

[0091] - disodium hydrogen phosphate dihydrate at a concentration of about 0.85 mg / mL;

[0092] - sodium chloride at a concentration of about 8.6 mg / mL; and

[0093] - Water, and

[0094] The total weight of Ensefentin in the liquid pharmaceutical composition is about 3.0 mg.

[0095] 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 may be about 2.5 mL.

[0096] The present invention also provides a liquid pharmaceutical composition, which comprises, relative to the total weight of the liquid pharmaceutical composition:

[0097] - Ensephentin particles at a concentration of 1.0 to 1.4 mg / mL, the Ensephentin particles having a Dv10 of about 0.3 to 0.9 μm, a Dv50 of about 1.0 to 2.2 μm, and a Dv90 of about 2.3 to 4.5 μm;

[0098] - Polysorbate 20 (Tween 20) at a concentration of 0.3 to 0.7 mg / mL;

[0099] -sorbitan monolaurate (Span 20) at a concentration of 0.0 to 0.1 mg / mL;

[0100] - sodium dihydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg / mL;

[0101] - disodium hydrogen phosphate dihydrate at a concentration of 0.5 to 1.0 mg / mL;

[0102] - sodium chloride at a concentration of 5 to 10 mg / mL; and

[0103] - Water, and

[0104] The total weight of Ensefentin in the liquid pharmaceutical composition is 2.7 to 3.3 mg. The liquid pharmaceutical composition may be as further defined herein.

[0105] The ampoule typically contains 2.0 to 3.0 mL of a liquid drug composition. The nebulizer contains a liquid drug composition, and the liquid drug composition is typically contained in an 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. PRO Aerosol Delivery System PARI PARI LC Sprint Jet Nebulizer for Compressor.

[0106] A method of 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.

[0107] COPD is usually moderate COPD or severe COPD. The above stages of COPD can be classified as follows, where FEV1 is the forced expiratory volume in 1 second and FVC is the forced vital capacity.

[0108] Mild COPD: FEV1 / FVC < 0.7 and FEV1 ≥ 80% predicted

[0109] Moderate COPD: FEV1 / FVC < 0.7 and 50% ≤ FEV1 < 80% predicted

[0110] Severe COPD: FEV1 / FVC < 0.7 and 30% ≤ FEV1 < 50% predicted

[0111] Very severe COPD: FEV1 / FVC<0.7 and FEV1<30% predicted In each case, the actual FEV1 of the human individual is compared with the predicted FEV1 value based on factors such as the age and height of the human individual. These predicted values ​​are readily available to 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 (spirometry reference values ​​from a sample of the general US population). AM J Respir Crit Care 1999; 159: 179-187). An example of an equation for calculating the predicted FEV1 (in L) of a human individual is as follows, where H is height (cm) and A is age (years):

[0112] ·Male: 0.0430H-0.0290A-2.490

[0113] ·Female: 0.0395H-0.025A-2.600

[0114] FEV1 and FVC used to determine the severity of COPD in human individuals are measured by spirometry shortly after administration of an adequate dose of at least one short-acting inhaled bronchodilator. Typically, measurements of FEV1 and FVC used to determine COPD disease severity are performed 15 to 30 minutes after administration of albuterol.

[0115] Typically, FEV1 and FVC as used herein are measured as described in Standardisation of Spirometry Eur J 2005; 26; 319-338

[0116] A human subject has been determined to have moderate COPD by measuring FEV1 / FVC<0.7 and 50%≤FEV1<80% predicted FEV1 values, wherein FEV1 is the forced expiratory volume in 1 second and FVC is the forced vital capacity measured 15 to 30 minutes after administration of a bronchodilator, optionally wherein the bronchodilator is albuterol. A human subject has been determined to have severe COPD by measuring FEV1 / FVC<0.7 and 30%≤FEV1<50% predicted, wherein FEV1 is the forced expiratory volume in 1 second and FVC is the forced vital capacity measured 15 to 30 minutes after administration of a bronchodilator, optionally wherein the bronchodilator is albuterol. Determining the severity of COPD in a human subject can be performed at least 1 day prior to the first administration of the compound.

[0117] The human subject may be male. The human subject may be female. The human subject may be greater than or equal to 65 years of age. The human subject may be less than 65 years of age. The human subject may take one or more background medications selected from a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), and an inhaled corticosteroid (ICS). In some cases, the human subject does not receive background medications. For example, the human subject may not take background medications, which are long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA), or inhaled corticosteroids (ICS).

[0118] Preferably, the method comprises administering the compound to a human subject by inhalation from a nebulizer. A nebulizer aerosolizes a liquid pharmaceutical composition into an aerosol which is inhaled into the respiratory tract of a human subject. Examples of nebulizers include soft mist nebulizers, vibrating mesh nebulizers, jet nebulizers, and ultrasonic nebulizers. Suitable nebulizer devices include the Philips I-neb TM(Philips)、Philips SideStream(Philips)、 (Philips), Philips InnoSpireGo (Philips), Pari LC sprint (Pari GmbH), AERxR TM Pulmonary delivery system (Aradigm Corp) and PariLC Plus reusable nebulizer (Pari GmbH). The nebulizer can be, for example, a PARI PRO Aerosol Delivery System PARI The compound may be inhaled via the nebulizer for 1 to 15 minutes, such as 5 to 10 minutes, or about 7 minutes.

[0119] Typically, the method includes 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 includes administering the compound to a human subject by inhalation twice a day. The method may include administering a first dose of the compound in the morning (e.g., within 3 hours after waking up) and administering a second dose of the compound in the evening (e.g., 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.

[0120] Typically, the compound is administered twice a day in two separate doses that are the same or similar. Typically, the method may comprise administering the compound to a human subject twice a day in a first dose of 2 to 4 mg and a second dose of 2 to 4 mg.

[0121] Preferably, the method comprises administering to a human subject two doses of a liquid pharmaceutical composition comprising about 3 mg of ensifentin free base per day by inhalation. The method preferably comprises administering to a human subject about 3 mg doses of the compound twice a day (3 mg BID) by inhalation. More preferably, the method comprises administering to a human subject about 3 mg doses of the compound twice a day by nebulizer. Each dose may be 3.0 mg of free base ensifentin administered by nebulizer.

[0122] The compound is typically used as a maintenance therapy. Typically, the method comprises administering the compound to a human subject at least once a day for at least 8 weeks. The compound may be administered to a human subject at least once a day for at least 16 weeks, preferably at least 24 weeks. The compound may be administered to a human subject daily for at least 1 year. The method may comprise administering the compound to a human subject 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.

[0123] The liquid pharmaceutical composition is administered to a human subject by inhalation to provide a plasma concentration of encefantine having a mean C of about 400 pg / mL to about 720 pg / mL. max and / or a mean AUC of about 2000 pg / mL*h to about 3000 pg / mL*h 0-tau and / or an average T of about 0.8 hours to about 1.3 hours max The average pharmacokinetic profile (or the pharmacokinetic profile achieved in individual human subjects) may be further defined as above for the liquid pharmaceutical composition.

[0124] Administration of liquid pharmaceutical compositions to human subjects by inhalation generally provides a mean increase in baseline FEV1 of at least 20 mL.

[0125] The invention also provides a liquid pharmaceutical composition as defined herein for use in a method of treating COPD as defined herein. Also provided is the use of a liquid pharmaceutical composition as defined herein in the preparation of a medicament for use in a method of treating COPD as defined herein.

[0126] The present invention is described in more detail by the following examples. Example

[0127] Study Design

[0128] A clinical study was conducted to determine the efficacy of Ensefentin in the treatment of COPD compared to placebo. Ensefentin was administered twice a day (BID) at a dose of 3 mg via nebulizer for 24 weeks. The study was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial with approximately 800 patients and 5:3 randomization.

[0129] The study population included patients aged 40 to 80 years with moderate to severe COPD (FEV1 30% to 70% pn, FEV1 / forced vital capacity (FVC) ratio <0.7, mMRC ≥2). Randomization was stratified by (a) use of stable background maintenance LAMA or LABA therapy (approximately 50%, yes or no) and (b) smoking (current or former). Inhaled corticosteroid (ICS) maintenance therapy was allowed in up to 20% of patients under certain provisions.

[0130] The primary endpoint of the study was the mean FEV1 area under the curve (AUC) compared with baseline at week 12. 0-12h Secondary endpoints of the study included: peak FEV1 at 4 hours at week 12 after dosing; morning trough FEV1 at week 12; and other endpoints, including the frequency of moderate / severe COPD exacerbations through 24 weeks.

[0131] method

[0132] Baseline FEV1 was the average of two measurements taken ≤40 minutes before the first dose of study drug on the day of administration and just before dosing on the first day.

[0133] Mean FEV1 AUC 0-12h It is defined as the area under the curve of FEV1 over 12 hours divided by 12 hours.

[0134] Plasma concentrations of encefantine for evaluation of pharmacokinetic (PK) parameters were measured using a validated bioanalytical method for encefantine in human plasma, with an LLOQ of 5 pg / mL for encefantine.

[0135] The samples were processed according to the following scheme:

[0136] Week 6: 1.0 h (± 0.5 h) and 2.5 h (± 0.5 h) (even-numbered sites) or 1.5 h and 4 h (± 1 h) (odd-numbered sites);

[0137] Week 12: before dosing (-0.5 h), 4 to 6 h, and 8 to 12 h (even-numbered sites) or 0.5 h (±0.25 h), 3 h (±0.5 h), and 6 to 8 h (odd-numbered sites);

[0138] Week 24: before dosing (-0.5h) and 1.5h (even-numbered sites) or before dosing (-0.5h) and 1h (±0.5h) (odd-numbered sites)

[0139] preparation

[0140] The study product and placebo were provided in 2.5 mL unit dose form in ampoules and administered by nebulizer. The formulations of the study product (ensefentin suspension formulation comprising ensefentin crystalline polymorph Form I) and placebo are shown in Table 1 below.

[0141]

[0142]

[0143] Table 1

[0144] result

[0145] Mean FEV1 (AUC) achieved at week 12 0-12h All subgroups showed an improvement in lung function with ensefentin, which was statistically significant. The results are shown in Table 2.

[0146]

[0147] Table 2

[0148] Based on the samples collected during the trial, the PK data of COPD patients with normal renal function are modeled. The final popPK model is used to predict the parameter estimation in the virtual population (each covariation condition) of 50000 individuals, for simulating the PK of ensefentin in the population with normal renal function or mild renal injury or moderate renal injury in the test after atomization 3mg. The uncertainty and residual variability of fixed effect and covariance matrix parameters are considered in the simulation. 500 groups of parameter estimates from the bootstrap (750 repetitions) in R are used to create 500NONMEM simulation control flows to consider parameter uncertainty. From each group of parameter estimation, the PK curves of 100 individuals (for each covariate condition) are simulated with the residual error in IIV and IOV from the covariance matrix and NONMEM. Each individual concentration is simulated using 7.4.3 version NONMEM, and PK parameters are calculated using 3.4.0 version R.

[0149] The results are shown in Table 3.

[0150] Parameter (unit) Median (90% prediction interval) <![CDATA[C max (pg / mL)]]> 522(173-1330) <![CDATA[AUC 0-tau (pg / mL*h)]]> 2450(882-7500) <![CDATA[T max (Hours)]]> 1.0

[0151] Table 3

[0152] in conclusion

[0153] It has been found that Ensefentin provided statistically significant improvements in lung function in all subgroups of COPD patients in the study.

[0154] The average C of COPD patients max The mean AUC was 522 pg / mL and the mean AUC was 2450 pg / mL*h. These values ​​are lower than the mean C observed after administration of the composition to healthy patients. max (852 pg / mL) and mean AUC (mean AUC 0-∞ This indicates that the systemic exposure of ensefentin in COPD patients is lower than that in healthy patients.

Claims

1. A liquid pharmaceutical composition comprising a dose of a compound, wherein the compound is ensefentin or a pharmaceutically acceptable salt thereof, wherein the liquid pharmaceutical composition provides, upon administration by inhalation to a human subject suffering from COPD, a plasma concentration of encefantine having: Average C from about 400 pg / mL to about 720 pg / mL max ; and / or Average AUC from about 2000 pg / mL*h to about 3000 pg / mL*h 0-tau ; and / or Average T of about 0.6 hours to about 1.5 hours max .

2. The liquid pharmaceutical composition of claim 1, wherein the liquid pharmaceutical composition provides a mean C of about 400 pg / mL to about 720 pg / mL after administration by inhalation to a human subject suffering from COPD. max Plasma concentrations of ensefentin.

3. The liquid pharmaceutical composition of claim 2, wherein the average C max From about 500 pg / mL to about 600 pg / mL.

4. A liquid pharmaceutical composition according to any of the preceding claims, wherein the liquid pharmaceutical composition provides a mean AUC of about 2000 pg / mL*h to about 3000 pg / mL*h after administration by inhalation to a human subject suffering from COPD 0-tau Plasma concentrations of ensefentin.

5. The liquid pharmaceutical composition of claim 4, wherein the mean AUC 0-tau It is about 2300 pg / mL*h to about 2600 pg / mL*h.

6. A liquid pharmaceutical composition according to any preceding claim, wherein the liquid pharmaceutical composition has a mean T of about 0.6 hours to about 1.5 hours after administration by inhalation to a human subject suffering from COPD max Plasma concentrations of ensefentin.

7. The liquid pharmaceutical composition of claim 6, wherein the average T max From about 0.8 hours to about 1.3 hours.

8. The liquid pharmaceutical composition of any preceding claim, wherein the liquid pharmaceutical composition provides a plasma concentration of encefantine after administration by inhalation to a human subject suffering from COPD, the plasma concentration of encefantine being: Average C of about 500 pg / mL to about 600 pg / mL max ;and Mean AUC from about 2350 pg / mL*h to about 2550 pg / mL*h 0-tau ;and Average T of about 0.8 hours to about 1.3 hours max .

9. A liquid pharmaceutical composition as claimed in any preceding claim, wherein the average C max , average AUC 0-tau and average T max is measured by determining the plasma concentration in samples from human subjects with COPD at intervals following administration of the liquid pharmaceutical composition, Optionally, the interval is two or more of 1.0 h (± 0.5 h), 1.5 h (± 0.5 h), 2.5 h (± 0.5 h), 3.0 h (± 0.5 h), 4.0 h (± 1 h), 6.0 h (± 1 h), 8.0 h (± 1 h), 10.0 h (± 1 h), 12.0 h (± 1 h), 24.0 h (± 1 h), 36.0 h (± 1 h), 48.0 h (± 1 h), 56.0 h (± 1 h) and 60.0 h (± 1 h) after administration of the liquid pharmaceutical composition.

10. The liquid pharmaceutical composition of claim 9, wherein the plasma concentration is determined using an analytical method with a LLOQ of no greater than about 5.0 pg / mL.

11. A liquid pharmaceutical composition according to any preceding claim, wherein the dose of the compound is from about 2.5 mg to about 3.5 mg.

12. A liquid pharmaceutical composition according to any preceding claim, wherein the dose of the compound is about 3.0 mg.

13. The liquid pharmaceutical composition of any preceding claim, wherein the liquid pharmaceutical composition provides a mean increase in baseline FEV1 of at least 20 mL following administration by inhalation to a human subject.

14. A liquid pharmaceutical composition according to any preceding claim, wherein the liquid pharmaceutical composition comprises (a) a suspension of particles comprising the compound and (b) a diluent.

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

16. The liquid pharmaceutical composition of claim 14 or 15, wherein particles comprising the compound have a Dv50 of about 1.0 μm to about 2.2 μm.

17. The liquid pharmaceutical composition of any one of claims 14 to 16, wherein particles comprising 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 any one of claims 14 to 17, wherein the particles comprising the compound are particles comprising at least 95% by weight of encefantine.

19. The liquid pharmaceutical composition according to any of the preceding claims, wherein the liquid pharmaceutical composition comprises, relative to the total weight of the liquid pharmaceutical composition: (i) Ensephentin particles at a concentration of 0.8 to 1.6 mg / mL, the Ensephentin particles having a Dv50 of about 1.0 μm to about 2.2 μm, and optionally having 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 buffering agents at a total concentration of 1.0 to 2.0 mg / ml; and (iv) Water.

20. The liquid pharmaceutical composition of any preceding claim, wherein the liquid pharmaceutical composition comprises, relative to the total weight of the liquid pharmaceutical composition: - Ensephentin particles at a concentration of 1.0 to 1.4 mg / mL, the Ensephentin particles having a Dv10 of about 0.3 to about 0.9 μm, a Dv50 of about 1.0 to about 2.2 μm, and a Dv90 of about 2.3 to about 4.5 μm; - Polysorbate 20 (Tween 20) at a concentration of 0.3 to 0.7 mg / mL; - Sorbitan monolaurate (Span 20) at a concentration 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 at a concentration of 5 to 10 mg / mL; and - Water, and The total weight of encefantine in the liquid pharmaceutical composition is 2.7 to 3.3 mg.

21. The liquid pharmaceutical composition of any preceding claim, wherein the liquid pharmaceutical composition comprises, relative to the total weight of the liquid pharmaceutical composition: - Ensefentin particles at a concentration of about 1.2 mg / mL, the Ensefentin particles having a Dv10 of 0.4 to 0.7 μm, a Dv50 of 1.2 to 1.9 μm, and a Dv90 of 2.9 to 4.3 μm; - Polysorbate 20 (Tween 20) at a concentration of about 0.5 mg / mL; - Sorbitan monolaurate (Span 20) at a concentration of about 0.05 mg / mL; - sodium dihydrogen phosphate dihydrate at a concentration of about 0.744 mg / mL; - disodium hydrogen phosphate dihydrate at a concentration of about 0.853 mg / mL; - sodium chloride at a concentration of about 8.6 mg / mL; and - Water, and The total weight of Ensefentin in the liquid pharmaceutical composition is about 3.0 mg.

22. The liquid pharmaceutical composition of any one of claims 19 to 21, wherein the encefantine particles comprise at least 90% by weight of encefantine in the form of crystalline polymorph Form I, wherein the crystalline polymorph Form I has a powder X-ray diffraction pattern comprising at least 5 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 any one of the preceding claims, wherein the total volume of the liquid pharmaceutical composition is 2.0 to 3.0 mL, preferably wherein the total volume of the liquid pharmaceutical composition is about 2.5 mL.

24. A liquid pharmaceutical composition as claimed in any preceding claim, wherein the human subject suffers from moderate COPD or severe COPD.

25. An ampoule comprising a liquid pharmaceutical composition as defined in any preceding claim.

26. A nebulizer comprising a liquid pharmaceutical composition as defined in any one of claims 1 to 24.

27. A method of treating COPD in a human subject, said method comprising administering to said human subject by inhalation a liquid pharmaceutical composition as defined in any one of claims 1 to 24.

28. The method of claim 27, wherein the COPD is moderate COPD or severe COPD.

29. The method of claim 27 or 28, wherein administering the liquid pharmaceutical composition to the human subject by inhalation provides a plasma concentration of encefantine having: Average C from about 400 pg / mL to about 720 pg / mL max ; and / or Average AUC from about 2000 pg / mL*h to about 3000 pg / mL*h 0-tau ; and / or Average T of about 0.8 hours to about 1.3 hours max .

30. The method of any one of claims 27 to 29, wherein administering the liquid pharmaceutical composition to the human subject by inhalation provides a mean increase in baseline FEV1 of at least 20 mL.

31. A liquid pharmaceutical composition as defined in any one of claims 1 to 24 for use in a method of treating COPD as defined in any one of claims 27 to 30.

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