Liquid pharmaceutical compositions comprising enfenthrin and glycopyrrolate

Abstract

To provide a liquid pharmaceutical composition comprising ensifentine and glycopyrrolate, wherein both compounds are stable.SOLUTION: (i) ensifentinib particles; (ii) glycopyrrolate; and (iii) a diluent comprising water; wherein: Wherein the glycopyrrolate is dissolved in the diluent; the concentration of glycopyrrolate is 5.0 mg / ml or less; and the pH of the liquid pharmaceutical composition is 3.0 to 6.0. The present invention also provides a nebulizer comprising the liquid pharmaceutical composition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to an inhalable liquid pharmaceutical composition comprising ensifentrine and glycopyrrolate. The present invention also relates to a nebulizer comprising said liquid pharmaceutical composition. [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 bronchodilatory and anti-inflammatory properties and is useful in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). The structure of ensifentrine is shown below.

[0004] [ka]

[0005] WO2016 / 042313A describes a formulation of ensifentrine as a suspension of particles in an aqueous diluent.

[0006] Ensifentrine may be used in combination with glycopyrrolate, a muscarinic receptor antagonist. As used herein, "glycopyrrolate" refers to a salt containing the cation glycopyrronium. Glycopyrronium has the formula (1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate. The structure of glycopyrronium is shown below.

[0007] [ka]

[0008] Combination of ensifentrine and glycopyrrolate useful for treating respiratory disorders - Patents.com is described in WO2014 / 140648A.

[0009] The formulation of pharmaceutical compounds is complex and unpredictable. This is especially true for liquid pharmaceutical compositions for inhalation administration. For example, such inhalable liquid pharmaceutical compositions must be sufficiently stable so that a reasonably consistent dose can be delivered during inhalation even after a certain period of storage. The difficulties associated with the preparation of inhalable pharmaceutical compositions are exacerbated when the composition contains two active agents, such as the combination of ensifentrine and glycopyrrolate. For such combined formulations, the stability of both pharmaceutical compounds must be controlled.

[0010] There is a need to develop a liquid pharmaceutical composition comprising ensifentrine and glycopyrrolate in which both compounds are stable. It is also desirable to prepare a liquid pharmaceutical composition suitable for administration by inhalation. Summary of the Invention

[0011] It is a surprising discovery of the present invention that a pharmaceutical composition in which both ensifentrine and glycopyrrolate are stable can be produced by formulating ensifentrine as a suspension of particles and glycopyrrolate as a solution in a low pH aqueous diluent, with the concentration of glycopyrrolate being low relative to the concentration of ensifentrine. This particular formulation, in which ensifentrine is suspended and glycopyrrolate is dissolved, has been shown to be stable with respect to chemical degradation of both active agents after storage for at least three months.

[0012] The present invention therefore provides a liquid pharmaceutical composition suitable for administration by inhalation, comprising: (i) ensifentrine particles; (ii) glycopyrrolate; and (iii) a diluent comprising water, wherein: the glycopyrrolate is dissolved in the diluent; the concentration of glycopyrrolate is 5.0 mg / mL or less; and the pH of the liquid pharmaceutical composition is 3.0 to 6.0.

[0013] The present invention also provides a nebulizer comprising a liquid pharmaceutical composition according to the present invention.

[0014] Further provided by the present invention is a liquid pharmaceutical composition according to the present invention for use in the treatment of the human or animal body. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description of the Invention The liquid pharmaceutical composition comprises glycopyrrolate. Glycopyrrolate is typically present in the liquid pharmaceutical composition as a pharmaceutically acceptable salt of glycopyrronium. Glycopyrrolate is typically glycopyrronium bromide, although other pharmaceutically acceptable salts of glycopyrronium, such as glycopyrronium chloride, may be used. Glycopyrrolate is preferably glycopyrronium bromide.

[0016] Glycopyrrolate is dissolved in the diluent. Thus, at least some (e.g., at least 50% by weight) of the total mass of glycopyrrolate present in the liquid pharmaceutical composition is dissolved in the diluent. Typically, substantially all of the glycopyrrolate is dissolved in the diluent. For example, at least 99.0% by weight of glycopyrrolate, based on the total mass of glycopyrrolate in the liquid pharmaceutical composition, may be dissolved in the diluent. The term "dissolved" takes its ordinary meaning in the art, for example, glycopyrrolate is in solution in the diluent and cannot be recovered by standard filtration.

[0017] The pharmaceutical composition is a liquid pharmaceutical composition and, as such, is liquid under ambient conditions (eg, at a temperature of from 10 to 40° C.).

[0018] The pH of the liquid pharmaceutical composition is 3.0 to 6.0. Typically, the pH of the liquid pharmaceutical composition is 3.5 to 5.0. For example, the pH of the liquid pharmaceutical composition may be 4.3 to 4.7. The pH of the liquid pharmaceutical composition may be 3.5 to 4.5, for example, 3.8 to 4.2.

[0019] The pH of a liquid pharmaceutical composition is typically measured at a temperature of 20° C. The pH of a liquid pharmaceutical composition may be measured by any suitable technique. For example, the pH may be measured using a potentiometric pH meter.

[0020] The liquid pharmaceutical composition typically further comprises a buffer solution. The buffer solution can be used to control the pH of the liquid pharmaceutical composition. The buffer solution typically comprises a weak acid and its conjugate base. Examples of buffer solutions include citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer.

[0021] Preferably, the buffer solution is a citrate buffer solution. The citrate buffer solution typically contains citric acid and a citrate salt. For example, the citrate buffer solution may contain citric acid and trisodium citrate. The citric acid may be citric acid monohydrate. The trisodium citrate may be trisodium citrate dihydrate.

[0022] The buffer concentration is typically 10.0 to 40.0 mg / mL. Preferably, the buffer concentration is 20.0 to 30.0 mg / mL. The buffer concentration includes both the acid and conjugate base components of the buffer.

[0023] The concentration of glycopyrrolate in the liquid pharmaceutical composition is 5.0 mg / mL or less. For example, the concentration of glycopyrrolate can be 0.001 to 5.0 mg / mL. Typically, the concentration of glycopyrrolate is 0.01 mg / mL to 2.0 mg / mL, for example, 0.01 to 1.0 mg / mL.

[0024] Preferably, the glycopyrrolate concentration is 0.02 mg / mL to 0.25 mg / mL. For example, the glycopyrrolate concentration can be 0.14 to 0.16 mg / mL. The glycopyrrolate concentration can be 0.02 to 0.03 mg / mL, for example, about 0.025 mg / mL (25 μg / mL).

[0025] The liquid pharmaceutical composition comprises ensifentrine particles. The ensifentrine particles comprise ensifentrine (i.e., ensifentrine free base) or a pharmaceutically acceptable salt thereof. Typically, the ensifentrine particles comprise ensifentrine. The ensifentrine particles typically comprise at least 90.0% by weight of ensifentrine or a pharmaceutically acceptable salt thereof, more preferably at least 95.0% by weight. The ensifentrine particles can consist essentially of ensifentrine or a pharmaceutically acceptable salt thereof, or can consist of ensifentrine or a pharmaceutically acceptable salt thereof. For example, the ensifentrine particles can consist of ensifentrine free base.

[0026] A composition that consists essentially of an ingredient typically contains only that ingredient and other ingredients that do not substantially affect the essential properties of the ingredient from which the composition consists. A composition that consists essentially of an ingredient may contain at least 99.5% by weight of that ingredient, based on the total weight of the composition.

[0027] The ensifentrine particles in the liquid pharmaceutical composition are typically suspended in a diluent. A liquid pharmaceutical composition therefore typically comprises a suspension of ensifentrine particles. Some or all of the ensifentrine particles in a liquid pharmaceutical composition may sink to the bottom of a container containing the liquid pharmaceutical composition, for example, after a period of storage. The ensifentrine particles may be resuspended by any suitable method, for example, by agitation of the liquid pharmaceutical composition.

[0028] The weight ratio of ensifentrine to glycopyrrolate in the liquid pharmaceutical composition can be 1:5 to 200:1. For example, for every gram of ensifentrine in the composition, 0.005 to 5.0 grams of glycopyrrolate can be present. Typically, the total concentration of ensifentrine in the liquid pharmaceutical composition is greater than the total concentration of glycopyrrolate in the liquid pharmaceutical composition. Preferably, the weight ratio of ensifentrine to glycopyrrolate in the liquid pharmaceutical composition is 5:1 to 150:1. The weight ratio of ensifentrine to glycopyrrolate in the liquid pharmaceutical composition can be 15:1 to 120:1, for example, 8:1 to 12:1.

[0029] The concentration of ensifentrine particles in the liquid pharmaceutical composition can be any suitable concentration, for example, 0.01 to 400 mg / mL. Typically, the concentration of ensifentrine particles is 0.1 to 5.0 mg / mL. Preferably, the concentration of ensifentrine particles is 0.1 to 2.5 mg / mL. For example, the concentration of ensifentrine particles can be 0.15 to 0.5 mg / mL or 1.0 to 2.0 mg / mL.

[0030] The ensifentrine particles typically have a Dv50 of 0.5 μm to 5.0 μm. The ensifentrine particles preferably have a Dv50 of 1.0 μm to 2.0 μm. Typically, the Dv10 of the ensifentrine particles is 0.2 μm to 1.0 μm, and the Dv90 of the ensifentrine particles is 2.5 μm to 6.0 μm. For example, the Dv10 of the ensifentrine particles can be 0.4 μm to 0.6 μm, and the Dv90 of the ensifentrine particles can be 2.8 μm to 3.8 μm.

[0031] 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 less than the Dv50 value, and half of the particle volume has a diameter greater 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 less than the Dv10 value. 90% of the particle volume has a diameter less than the Dv90 value.

[0032] The technique used to measure the Dv50 (and Dv10 and Dv90) values ​​described herein is typically laser diffraction.The particle size distribution of ensifentrine particles can be measured by laser diffraction using a wet powder dispersion system.For example, the particle size distribution can be measured by laser diffraction using a Malvern Spraytec in conjunction with a wet dispersion cell.Typically, the instrument parameters for Malvern Spraytec are as follows:

[0033] · 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 - specified time; First sampling time - 30 seconds; · Obfuscation -20%~30%. Dispersant - 1% Polysorbate 20 in deionized water.

[0034] 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 a solid form of ensifentrine, such as by air jet milling, mechanical micronization, or media milling.

[0035] The diluent comprises water. The diluent may comprise, for example, water and a secondary solvent such as ethanol. Typically, the liquid pharmaceutical composition comprises at least 50% by weight of water based on the total weight of the liquid pharmaceutical composition. Preferably, the diluent is water, and the liquid pharmaceutical composition comprises at least 80% by weight of the diluent based on the total weight of the liquid pharmaceutical composition. The diluent is typically sterile. The liquid pharmaceutical composition is typically sterile.

[0036] The liquid pharmaceutical composition typically further comprises an isotonicity agent. Examples of the isotonicity agent include sodium chloride, potassium chloride, glucose, glycerin and mannitol. Preferably, the isotonicity agent is sodium chloride.

[0037] The concentration of the tonicity agent is typically 1.0 mg / mL or more (e.g., 1.0 to 50.0 mg / mL). Preferably, the concentration of the tonicity agent is 4.0 to 20.0 mg / mL, more preferably 6.0 to 12.0 mg / mL.

[0038] The liquid pharmaceutical composition typically further comprises one or more surfactants. The one or more surfactants may comprise a nonionic surfactant, an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, or a mixture thereof. Typically, the one or more surfactants comprises a nonionic surfactant.

[0039] Examples of surfactants include lecithin, oleic acid, polyoxyethylene glycol alkyl ethers (e.g., PEG300, PEG600, PEG1000, Brij30, Brij35, Brij56, Brij76, and Brij97), polypropylene glycols (e.g., PPG2000), 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 97), and the like. Sorbitan alkyl esters (e.g., sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), and sorbitan trioleate (Span 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).

[0040] Preferably, the one or more surfactants include polysorbates and / or sorbitan alkyl esters. 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 alkyl esters. The liquid pharmaceutical composition may comprise polysorbate 20 and / or sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80) or sorbitan trioleate (Span 85). Preferably, the liquid pharmaceutical composition comprises polysorbate 20 and / or sorbitan monolaurate (Span 20).

[0041] The liquid pharmaceutical composition may contain two or more surfactants, or the liquid pharmaceutical composition may contain a single surfactant. For example, the composition may contain a single surfactant that is a polysorbate, such as polysorbate 20. The composition may contain two or more surfactants. For example, the liquid pharmaceutical composition may contain polysorbate 20 and sorbitan monolaurate (Span 20).

[0042] The total concentration of one or more surfactants is typically 0.01 to 2.0 mg / mL. Preferably, the total surfactant concentration is 0.1 to 1.0 mg / mL. For example, the total surfactant concentration in the liquid pharmaceutical composition may be 0.25 to 0.75 mg / mL. For example, the liquid pharmaceutical composition may contain a polysorbate at a concentration of 0.1 to 1.0 mg / mL and, optionally, a sorbitan alkyl ester at a concentration of 0.01 to 0.1 mg / mL.

[0043] Liquid pharmaceutical compositions typically comprise: (i) Ensifentrine particles; (ii) glycopyrrolate; (iii) diluents; (iv) polysorbate surfactants; (v) citrate buffer; and (vi) Sodium chloride Includes:

[0044] For example, a liquid pharmaceutical composition may comprise: (i) ensifentrine particles of 0.1 to 2.5 mg / mL, optionally ensifentrine particles of 0.5 to 2.5 mg / mL; (ii) 0.01 mg / mL to 2.0 mg / mL glycopyrronium bromide; (iii) water; (iv) 0.1 to 1.0 mg / mL polysorbate 20; (v) 5.0 to 15.0 mg / mL citric acid; (vi) 10.0 to 20.0 mg / mL trisodium citrate; and (vii) 5.0 to 15.0 mg / mL sodium chloride may include:

[0045] Liquid pharmaceutical compositions may, for example: (i) Ensifentrine particles; (ii) glycopyrrolate; (iii) diluents; (iv) polysorbate surfactants; (v) sorbitan alkyl ester surfactants; (vi) citrate buffer; and (vii) Sodium chloride may include:

[0046] For example, the liquid pharmaceutical composition may be (i) ensifentrine particles of 0.1 to 2.5 mg / mL, optionally ensifentrine particles of 0.5 to 2.5 mg / mL; (ii) 0.01 mg / mL to 2.0 mg / mL glycopyrronium bromide; (iii) water; (iv) 0.1 to 1.0 mg / mL polysorbate 20; (v) 0.01 to 0.1 mg / mL sorbitan monolaurate; (vi) 5.0 to 15.0 mg / mL citric acid; (vii) 10.0 to 20.0 mg / mL trisodium citrate; and (viii) 5.0 to 15.0 mg / mL sodium chloride may include:

[0047] The liquid pharmaceutical composition may consist of or consist essentially of components (i) through (vi), components (i) through (vii), or components (i) through (viii).

[0048] The liquid pharmaceutical composition is advantageously stable. In particular, the liquid pharmaceutical composition is typically stable with respect to chemical degradation of ensifentrine and glycopyrrolate for at least one month when stored at a temperature of 25° C. and a relative humidity of 60%. The liquid pharmaceutical composition may, for example, be stable under these conditions for at least three months.

[0049] Liquid pharmaceutical compositions can be prepared by standard pharmaceutical methods. Liquid pharmaceutical compositions are typically prepared by a method comprising dissolving glycopyrrolate in a diluent to prepare a glycopyrrolate solution, and mixing ensifentrine particles with the glycopyrrolate solution to prepare a suspension of ensifentrine particles. Alternatively, liquid pharmaceutical compositions can be prepared by a method comprising mixing ensifentrine particles with a diluent to prepare a suspension of ensifentrine particles, and then dissolving glycopyrrolate in the suspension.

[0050] Liquid pharmaceutical compositions are suitable for administration by inhalation. Typically, liquid pharmaceutical compositions are suitable for administration by a nebulizer.

[0051] The present invention provides a nebulizer containing a liquid pharmaceutical composition according to the present invention. The nebulizer is typically loaded with the liquid pharmaceutical composition. The nebulizer typically contains about 1.0 mL to about 200 mL, more typically 1.0 mL to 20 mL of the liquid pharmaceutical composition. The nebulizer preferably contains 2.0 mL to 5.0 mL of the liquid pharmaceutical composition, for example, about 2.5 mL.

[0052] Nebulizers aerosolize liquid pharmaceutical compositions into aerosols that are inhaled into the respiratory tract of a 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 These include Sprint (Pari GmbH), AERxR™ Pulmonary Delivery System (Aradigm Corp) and Pari LC Plus Reusable Nebuliser (Pari GmbH).

[0053] Ensifentrine is useful in the treatment of respiratory and inflammatory diseases. Glycopyrrolate is useful in the treatment of respiratory diseases. It has been found that ensifentrine and glycopyrrolate interact synergistically to cause relaxation of bronchial smooth muscle. The present invention provides a liquid pharmaceutical composition according to the present invention for use in the treatment of human or animal bodies. Typically, the liquid pharmaceutical composition is administered by inhalation.

[0054] Liquid pharmaceutical compositions are typically used to treat chronic obstructive pulmonary disease (COPD), asthma, allergic The compound is for use in the treatment or prevention of a disease or condition selected from asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin disease, atopic dermatitis, psoriasis, eye inflammation, cerebral ischemia, inflammatory disease, and autoimmune disease. Preferably, the disease or condition is COPD or asthma. More preferably, the disease or condition is chronic obstructive pulmonary disease (COPD).

[0055] The effective amount of ensifentrine is typically about 0.001 mg / kg to 50 mg / kg per single dose, for example, 0.01 mg / kg to 1 mg / kg per single dose. The effective amount of ensifentrine can be about 0.1 mg to about 500 mg, or about 0.1 mg to 100 mg, or about 0.1 mg to about 6 mg. A single dose of ensifentrine can be 0.3 mg to 3 mg.

[0056] An effective amount of glycopyrrolate is typically about 0.001 mg / kg to 25 mg / kg per single dose, for example, 0.001 mg / kg to 0.5 mg / kg per single dose. An effective amount of glycopyrrolate can be a dose of about 0.01 mg to about 250 mg, or about 0.02 mg to 3 mg. A single dose of glycopyrrolate can be 0.02 mg to 2.0 mg.

[0057] The liquid pharmaceutical composition may be administered once, twice, or three times daily, or two, three, four, or five times per week. For example, the pharmaceutical composition may be administered twice daily.

[0058] The present invention also provides the use of a liquid pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or condition as defined herein.

[0059] The present invention will now be described in more detail by the following examples. [Example]

[0060] method Assay and related substance testing was performed using high performance liquid chromatography with an acetonitrile:water mobile phase.

[0061] Example 1 - Preparation of Formulations Five pharmaceutical formulations (Formulations A to E) containing ensifentrine and glycopyrronium bromide (GP) were prepared.

[0062] The compositions of the five formulations are shown in Table 1.

[0063] [Table 1]

[0064] In each case, a suspension of particles of ensifentrine was first prepared in two media: (i) For Formulations A through C, an aqueous solution of polysorbate 20, sorbitan monolaurate, monosodium phosphate monohydrate, dibasic sodium phosphate anhydrous, and sodium chloride; or (ii) For formulations D and E, an aqueous solution of polysorbate 20, citric acid monohydrate, trisodium citrate dihydrate, and sodium chloride. It was prepared at a concentration of 1.5 mg / mL in one of the following solutions:

[0065] Glycopyrronium bromide was then dissolved in the ensifentrine suspension at a defined concentration (0.15 mg / mL, 1.5 mg / mL, or 15.0 mg / mL). The resulting formulation had the appearance of a pale yellow suspension with no visible aggregates after resuspension.

[0066] The pH of Formulations A through C was determined to be 6.7. The pH of Formulations D and E was determined to be 4.5.

[0067] Example 2 - Stability of formulations The stability of Formulations A through E with respect to chemical degradation of the active ingredient was evaluated. Five-mL samples of the formulations were stored in stoppered glass vials under three different conditions: (a) 25°C / 60% relative humidity (RH); (b) 40°C / 75% RH; and (c) 60°C. All formulations were tested after two weeks of storage under these conditions. Formulations D and E were further tested after three months of storage under these conditions.

[0068] The results of the stability evaluation after 2 weeks are shown in Table 2.

[0069] [Table 2]

[0070] The pH 6.7 phosphate buffer formulations (A, B, and C) were unstable under all conditions after 2 weeks, with glycopyrronium degradation observed. Formulation C after storage at 60°C showed significant degradation, and ensifentrine particles could not be resuspended even after vigorous shaking.

[0071] In contrast, Formulations D and E (pH 4.5 citrate buffer formulations) were more stable than Formulations A to C after 2 weeks. No degradation was observed for Formulation D after storage at 25°C / 60% RH or 40°C / 75% RH. Slight degradation of glycopyrronium was observed for Formulation D after storage at 60°C.

[0072] Some low level degradation of glycopyrronium was observed for Formulation E after storage at 25°C / 60% RH or 40°C / 75% RH, with more significant degradation observed after storage at 60°C.

[0073] Given the instability of Formulations A through C, further stability evaluation of those formulations was not performed. The stability of Formulations D and E was evaluated again at 3 months, and the results are shown in Table 3.

[0074] [Table 3]

[0075] Formulation D was found to be stable after 3 months of storage at both 25°C / 60% RH and 40°C / 75% RH. Slight degradation of glycopyrronium was observed after 3 months of storage at 60°C.

[0076] Some chemical degradation was observed after 3 months of storage at 25°C / 60% RH for Formulation E. More significant degradation was observed after 3 months of storage at 40°C / 75% RH and 60°C.

[0077] conclusion Of the five formulations tested, only Formulation D was observed to have adequate stability characteristics after storage. The inventors have therefore found that a low pH and a low glycopyrrolate concentration relative to the ensifentrine concentration are important for a stable formulation of a glycopyrrolate and ensifentrine combination for use as an inhalation product.

Claims

1. (i) ensifentrine particles; (ii) glycopyrrolate; and (iii) a diluent comprising water Including, Where: the glycopyrrolate is dissolved in the diluent; the concentration of glycopyrrolate is less than or equal to 5.0 mg / mL; and The pH of the liquid pharmaceutical composition is 3.0 to 6.

0. A liquid pharmaceutical composition suitable for administration by inhalation.

2. 10. The liquid pharmaceutical composition according to claim 1, wherein the pH of the liquid pharmaceutical composition is from 3.5 to 5.

0.

3. 3. The liquid pharmaceutical composition according to claim 1 or claim 2, wherein the liquid pharmaceutical composition further comprises a buffer, preferably a citrate buffer.

4. 4. The liquid pharmaceutical composition according to any one of claims 1 to 3, wherein the concentration of the buffer is from 10.0 to 40.0 mg / mL, preferably from 20.0 to 30.0 mg / mL.

5. 10. The liquid pharmaceutical composition according to any one of the preceding claims, wherein the concentration of glycopyrrolate is from 0.01 mg / mL to 2.0 mg / mL, preferably from 0.02 mg / mL to 0.25 mg / mL.

6. 10. A liquid pharmaceutical composition according to any one of the preceding claims, wherein the weight ratio of ensifentrine:glycopyrrolate in the liquid pharmaceutical composition is from 1:5 to 200:1, preferably from 15:1 to 120:

1.

7. 10. The liquid pharmaceutical composition according to any one of the preceding claims, wherein the concentration of the ensifentrine particles is from 0.1 to 5.0 mg / mL, preferably from 0.15 to 2.5 mg / mL.

8. 10. A liquid pharmaceutical composition according to any one of the preceding claims, wherein the ensifentrine particles have a Dv50 of 0.5 to 5.0 μm.

9. glycopyrrolate is a pharmaceutically acceptable salt of glycopyrronium; Preferably, the glycopyrrolate is glycopyrronium bromide or glycopyrronium chloride; More preferably, the liquid pharmaceutical composition according to any one of the preceding claims, wherein the glycopyrrolate is glycopyrronium bromide.

10. 10. A liquid pharmaceutical composition according to any one of the preceding claims, wherein the diluent is water and the liquid pharmaceutical composition comprises at least 80% by weight of the diluent, based on the total weight of the liquid pharmaceutical composition.

11. 10. A liquid pharmaceutical composition according to any one of the preceding claims, wherein the liquid pharmaceutical composition further comprises an isotonicity agent, preferably said isotonicity agent being sodium chloride.

12. 12. The liquid pharmaceutical composition according to claim 11, wherein the concentration of the isotonicity agent is 1.0 mg / mL or more, preferably 4.0 to 20.0 mg / mL, more preferably 6.0 to 12.0 mg / mL.

13. 10. A liquid pharmaceutical composition according to any one of the preceding claims, wherein the liquid pharmaceutical composition further comprises one or more surfactants, preferably the one or more surfactants are selected from polysorbates and sorbitan alkyl esters.

14. 14. The liquid pharmaceutical composition according to claim 13, wherein the total concentration of the one or more surfactants is from 0.01 to 2.0 mg / mL, preferably from 0.1 to 1.0 mg / mL.

15. 1. A liquid pharmaceutical composition comprising: (i) ensifentrine particles; (ii) glycopyrrolate; (iii) Diluent (iv) polysorbate surfactants; (v) optionally a sorbitan alkyl ester surfactant; (vi) citrate buffer; and (vii) sodium chloride 10. The liquid pharmaceutical composition according to any one of the preceding claims, comprising:

16. 1. A liquid pharmaceutical composition comprising: (i) 0.1 to 2.5 mg / mL ensifentrine particles, optionally 0.5 to 2.5 mg / mL ensifentrine particles; (ii) 0.01 mg / mL to 2.0 mg / mL glycopyrronium bromide; (iii) water; (iv) 0.1 to 1.0 mg / mL polysorbate 20; (v) optionally 0.01 to 0.1 mg / mL sorbitan monolaurate; (vi) 5.0 to 15.0 mg / mL citric acid; (vii) 10.0 to 20.0 mg / mL trisodium citrate; and (viii) 5.0 to 15.0 mg / mL sodium chloride 10. The liquid pharmaceutical composition according to any one of the preceding claims, comprising:

17. 10. A liquid pharmaceutical composition according to any one of the preceding claims, wherein the liquid pharmaceutical composition is stable with respect to chemical degradation of ensifentrine and glycopyrrolate for at least one month when stored at a temperature of 25°C and a relative humidity of 60%.

18. 10. A liquid pharmaceutical composition according to any one of the preceding claims, wherein the liquid pharmaceutical composition is suitable for administration by means of a nebulizer.

19. A nebulizer comprising a liquid pharmaceutical composition according to any one of the preceding claims.

20. 20. A liquid pharmaceutical composition according to any one of claims 1 to 18 for use in the treatment of the human or animal body.

21. 20. A liquid pharmaceutical composition according to any one of claims 1 to 18 for use in the treatment or prevention of a disease or condition selected from chronic obstructive pulmonary disease (COPD), asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, pulmonary fibrosis, interstitial lung disease, skin diseases, atopic dermatitis, psoriasis, eye inflammation, cerebral ischemia, inflammatory diseases and autoimmune diseases.

22. 22. The liquid pharmaceutical composition for use according to claim 21, wherein the disease or condition is chronic obstructive pulmonary disease (COPD).

23. 23. A method for treating or preventing a disease or condition as defined in claim 21 or claim 22 in a subject in need thereof, the method comprising administering to the subject an effective amount of a liquid pharmaceutical composition described in any one of claims 1 to 18.

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