Pharmaceutical Compositions Comprising Ensifentrine

Abstract

The present invention relates to a dry powder pharmaceutical composition suitable for inhalation administration, comprising (i) ensifentrine particles, (ii) coarse lactose particles having a Dv50 of 40 μm to 80 μm, and (iii) fine lactose particles having a Dv50 of 5 μm to 10 μm, wherein the fine lactose particles are present in an amount of 0.1% to 6.0% by weight based on the total weight of the dry powder pharmaceutical composition. A dry powder inhaler containing the dry powder pharmaceutical composition and medical uses of the dry powder pharmaceutical composition are also provided.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a dry powder pharmaceutical composition comprising a respiratory medicament. The present invention also relates to a dry powder inhaler comprising the dry powder pharmaceutical composition. [Background technology]

[0002] 2. Background of the Invention Ensifentrine (9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one; also known as RPL554) is a dual PDE3 / PDE4 inhibitor and is described in WO 00 / 58308 A1. Ensifentrine, a combined PDE3 / PDE4 inhibitor, has both anti-inflammatory and bronchodilatory properties and is useful in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). The structure of ensifentrine is shown below.

[0003] [ka]

[0004] Considering its effectiveness in treating respiratory diseases, ensifentrine is typically administered by inhalation.The administration of ensifentrine by nebulizer is known (WO 2016 / 042313 A1).However, it is often desirable to administer respiratory drugs using a handheld inhaler, such as a dry powder inhaler (DPI).

[0005] It is important that dry powder pharmaceutical formulations can be used in DPIs to effectively deliver the appropriate dose of active agent. Effective formulations for DPIs typically deliver a high fine particle fraction (FPF, corresponding to the proportion of the emitted dose with a particle size of less than 5 μm). WO 00 / 58308 A1 describes a dry powder formulation containing ensifentrine and lactose. WO 2014 / 140647 A1 describes a dry powder composition comprising an ensifentrine / beta-adrenergic receptor antagonist combination and a mixed lactose containing at least 15% lactose particles with a mass median diameter (MMD) of less than 15 μm.

[0006] There is a need to develop a dry powder formulation that effectively delivers ensifentrine. It is also desirable to prepare a dry powder formulation that can deliver a wide range of different ensifentrine doses. Summary of the Invention

[0007] Summary of the Invention It is a surprising discovery of the present invention that a dry powder composition comprising ensifentrine and a specific lactose blend that includes a low percentage of fine lactose having a specific particle size delivers an improved fine particle fraction, providing an improved method for administering ensifentrine by inhalation.

[0008] The present invention provides a dry powder pharmaceutical composition suitable for administration by inhalation comprising: (i) ensifentrine particles; (ii) coarse lactose particles having a Dv50 of 40 μm to 80 μm; and (iii) fine lactose particles having a Dv50 of 5 μm to 10 μm, wherein the fine lactose particles are present in an amount of 0.1% to 6.0% by weight based on the total weight of the dry powder pharmaceutical composition.

[0009] The present invention also provides a dry powder inhaler comprising a dry powder pharmaceutical composition of the present invention. Further provided by the present invention is a dry powder pharmaceutical composition of the present invention for use in treating the human or animal body. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Detailed Description of the Invention The dry powder pharmaceutical composition comprises fine lactose particles in an amount of 0.1% to 6.0% by weight relative to the total weight of the dry powder pharmaceutical composition. Typically, the amount of fine lactose particles is 0.5% to 5.0% by weight or 1.0% to 5.0% by weight relative to the total weight of the dry powder pharmaceutical composition. The amount of fine lactose may be 2.0% to 4.5% by weight. Preferably, the fine lactose particles are present in an amount of 3.5% to 4.0% by weight, such as about 3.75% by weight. Alternatively, the amount of fine lactose particles may be 0.25% to 1.0% by weight, such as about 0.5% by weight, or the amount of fine lactose particles may be 2.0% to 3.0% by weight, such as about 2.5% by weight.

[0011] Particle size is described herein with reference to the Dv50 value, which is the median particle size of the volume distribution. Thus, half of the volume of the particles has a diameter smaller than the Dv50 value, and half of the volume of the particles has a diameter larger than the Dv50 value. This is a well-known method for 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 the particles has a diameter less than the Dv10 value. 90% of the volume of the particles has a diameter less than the Dv90 value.

[0012] The technique used to measure the Dv50 (as well as Dv10 and Dv90) values ​​described herein is typically laser diffraction. For example, coarse lactose particles typically have a particle size distribution with a Dv50 value measured by laser diffraction of 40 μm to 80 μm, and fine lactose particles have a particle size distribution with a Dv50 value measured by laser diffraction of 5 μm to 10 μm.

[0013] The particle size distribution of poorly water-soluble materials, such as 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 combination with a wet dispersion cell. Typically, the instrument parameters for the Malvern Spraytec are as follows: · 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 – time; Initial sampling time – 30 seconds; ·Abscuration - 20%~30%; Dispersant – 1% Polysorbate 20 in deionized water.

[0014] The particle size distribution of water soluble raw materials, such as lactose particles, can be measured by laser diffraction using a dry powder dispersion system. For example, the particle size distribution can be measured by laser diffraction using a Malvern or Sympatec dry dispersion cell. An example of a Sympatec dry dispersion cell is the HELOS / BR laser diffraction sensor together with a RODOS dry dispersion unit. Measurement of the particle size of lactose is, for example, in accordance with the United States Pharmacopeia, 34th Edition, 2011, General Chapter, using ISO 13320:2009 Particle Size Analyses; Laser Diffraction Methods, Part 1: General Principles (2009). <429> "Optical Diffraction Measurement of Particle Size", United States Pharmacopoeia 34, 2011, General Chapter <429> , “Light diffraction measurement of particle size”, p 161).

[0015] The particles in the dry powder pharmaceutical composition of the present invention can be produced by any pharma- ceutically acceptable size reduction process or particle size control manufacturing process.For example, the particles can be produced by spray drying a solution, by controlled crystallization, or by size reduction of a solid, for example, by air jet milling, mechanical micronization, or media milling.Coarse and fine lactose particles can be produced, for example, by jet milling of lactose.

[0016] The fine lactose particles have a Dv50 of 5 μm to 10 μm. For example, the fine lactose particles may have a Dv50 of 5.0 μm to 10.0 μm. The fine lactose particles typically have a Dv10 value of 0.5 μm to 4.0 μm, for example, 1.0 μm to 3.0 μm. The fine lactose particles typically have a Dv90 value of 30 μm or less, for example, 10 μm to 30 μm.

[0017] The coarse lactose particles are typically present in an amount of 80.0% to 99.0% by weight, based on the total weight of the pharmaceutical composition. For example, the coarse lactose particles may be present in an amount of 90.0% to 96.0% by weight.

[0018] Coarse lactose particles typically have a Dv50 of 50 μm to 70 μm, preferably 55 μm to 65 μm. For example, the coarse lactose particles may have a Dv50 of about 60 μm.

[0019] The coarse lactose particles may comprise at least 95% by weight lactose or may consist essentially of lactose. The coarse lactose particles typically consist of lactose. The fine lactose particles may comprise at least 95% by weight lactose or may consist essentially of lactose. The fine lactose particles typically consist of lactose.

[0020] A composition consisting essentially of an ingredient typically contains only that ingredient and other ingredients that do not substantially affect the essential characteristics of the ingredient of which the composition consists essentially of. A composition consisting essentially of an ingredient may contain at least 99.5% by weight of that ingredient, based on the total weight of the composition.

[0021] The dry powder pharmaceutical composition comprises a blend comprising coarse and fine lactose particles. Thus, the particle size distribution of the lactose blend is bimodal, comprising two peaks, one corresponding to the modal particle size of the coarse lactose particles and one corresponding to the modal particle size of the fine lactose particles. As the skilled person will appreciate, there may be some overlap between the particle size distribution of the coarse lactose particles and the particle size distribution of the fine lactose particles in the lactose blend. For the avoidance of doubt, the lactose blend present in the dry powder pharmaceutical composition may be obtained by mixing said coarse lactose particles having a Dv50 of 40 μm to 80 μm with said fine lactose particles having a Dv50 of 5 μm to 10 μm.

[0022] The ensifentrine particles are typically present in an amount of 0.1% to 20% by weight, based on the total weight of the dry powder pharmaceutical composition. The amount of the ensifentrine particles is preferably 0.1% to 10% by weight. For example, the ensifentrine particles may be present in an amount of 0.2% to 6.0% by weight. The amount of the ensifentrine particles may be 2.0% to 4.5% by weight, or 3.5% to 4.0% by weight. For example, the amount of the ensifentrine particles may be about 2.5% by weight or about 3.75% by weight, based on the total weight of the dry powder pharmaceutical composition. Alternatively, the amount of the ensifentrine particles may be 0.1% to 0.5% by weight, for example about 0.25% by weight.

[0023] Typically, the amount (wt%) of ensifentrine particles present in the dry powder pharmaceutical composition is 40% to 120% of the amount (wt%) of fine lactose particles present in the dry powder pharmaceutical composition. For example, the amount (wt%) of ensifentrine particles can be 90% to 110% of the amount (wt%) of fine lactose particles present. In such a case, if 3.75 wt% of fine lactose particles are present, the amount of ensifentrine particles can be 3.375 wt% (90%) to 4.125 wt% (110%).

[0024] The ensifentrine particles include ensifentrine (i.e., ensifentrine free base) or a pharmaceutically acceptable salt thereof. Typically, the ensifentrine particles include ensifentrine. The ensifentrine particles typically include at least 90.0% by weight, more preferably at least 95.0% by weight, of ensifentrine or a pharmaceutically acceptable salt thereof. 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.

[0025] In some cases, the dry powder pharmaceutical composition comprises less than 0.1% by weight of a second active agent, which is a muscarinic receptor antagonist or a beta adrenergic receptor antagonist. For example, the dry powder pharmaceutical composition may not comprise a second active agent, which is a muscarinic receptor antagonist or a beta adrenergic receptor antagonist. In a preferred embodiment, ensifentrine is the only active agent in the dry powder pharmaceutical composition of the present invention.

[0026] The ensifentrin particles typically have a Dv50 of 0.5 μm to 5.0 μm. The ensifentrin particles preferably have a Dv50 of 1.0 μm to 2.0 μm. Typically, the Dv10 of the ensifentrin particles is 0.2 μm to 1.0 μm, and the Dv90 of the ensifentrin particles is 3.0 μm to 6.0 μm. For example, the Dv10 of the ensifentrin particles can be 0.4 μm to 0.6 μm, and the Dv90 of the ensifentrin particles can be 3.2 μm to 3.8 μm.

[0027] The dry powder pharmaceutical composition may include additional excipients. Typically, however, the main components of the dry powder pharmaceutical composition are ensifentrine particles, coarse lactose particles, and fine lactose particles. For example, the total amount of ensifentrine particles, coarse lactose particles, and fine lactose particles is typically at least 90.0% by weight, based on the total weight of the dry powder pharmaceutical composition. Preferably, the dry powder pharmaceutical composition includes at least 95.0% by weight of ensifentrine particles, coarse lactose particles, and fine lactose particles, based on the total weight of the dry powder pharmaceutical composition. The dry powder pharmaceutical composition may consist essentially of or consist of ensifentrine particles, coarse lactose particles, and fine lactose particles.

[0028] The dry powder pharmaceutical composition may comprise: (i) ensifentrine particles in an amount of 0.1% to 5.0% by weight; (ii) coarse lactose particles in an amount of 92.0% to 99.5% by weight; and (iii) fine lactose particles in an amount of 0.1% to 5.0% by weight, wherein these amounts are based on the total weight of the dry powder pharmaceutical composition.

[0029] The dry powder pharmaceutical composition may comprise: (i) ensifentrine particles in an amount between 0.1% and 0.4% by weight; (ii) coarse lactose particles in an amount between 99.0% and 99.5% by weight; and (iii) fine lactose particles in an amount between 0.25% and 0.75% by weight.

[0030] The dry powder pharmaceutical composition may comprise: (i) ensifentrine particles in an amount of 2.0% to 3.0% by weight; (ii) coarse lactose particles in an amount of 94.0% to 96.0% by weight; and (iii) fine lactose particles in an amount of 2.0% to 3.0% by weight.

[0031] The dry powder pharmaceutical composition may comprise: (i) ensifentrine particles in an amount of 3.5% to 4.0% by weight; (ii) coarse lactose particles in an amount of 92.0% to 93.0% by weight; and (iii) fine lactose particles in an amount of 3.5% to 4.0% by weight.

[0032] The dry powder pharmaceutical composition is typically suitable for administration by a dry powder inhaler. For example, the dry powder pharmaceutical composition may be suitable for administration by a capsule dry powder inhaler, a blister dry powder inhaler, or a reservoir dry powder inhaler.

[0033] The dry powder pharmaceutical composition can be prepared by standard formulation methods. For example, the dry powder pharmaceutical composition can be prepared by a method including mixing ensifentrine particles, coarse lactose particles and fine lactose particles. The ingredients can be mixed using a high shear mixer.

[0034] The present invention provides a dry powder inhaler (DPI) comprising the dry powder pharmaceutical composition defined herein. The DPI may be a blister DPI, a capsule DPI, or a reservoir DPI. DPIs are well known to those skilled in the art, and many such devices are commercially available, including Aerolizer Inc. TM (Novartis), Airmax TM (IV AX), ClickHaler TM (Innovata Biomed), Diskhaler TM (GlaxoSmithKline), Diskus TM or Accuhaler (GlaxoSmithKline), Easyhaler TM (Orion Pharma), Eclipse TM (Aventis), FlowCaps TM (Hovione), Handihaler TM (Boehringer Ingelheim), Pulvinal TM (Chiesi), Rotahaler TM (Glaxo Smith Kline), Skye Haler TM or Certihaler TM (SkyePharma), Twisthaler (Schering-Plough), Turbuhaler TM (AstraZeneca), Ultrahaler TM Representative dry powder inhaler devices include (Aventis), Plastiape RS01 Dry Powder Inhaler (RPC), Powdair (Hovione), MRX003 (Merxin) and MRX001 (Merxin).

[0035] The dry powder pharmaceutical composition is useful for treating the human or animal body. Ensifentrin is useful for treating respiratory and inflammatory diseases.

[0036] The present invention provides a dry powder pharmaceutical composition as defined herein for use in the treatment or prevention of a disease or condition selected from asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin disorders, atopic dermatitis, psoriasis, eye inflammation, cerebral ischemia, inflammatory diseases and autoimmune diseases. Typically, the dry powder composition is for use in the treatment of COPD or asthma. Preferably, the disease or condition is COPD.

[0037] Typically, the dry powder pharmaceutical composition is administered by inhalation from a DPI. The dry powder pharmaceutical composition is administered by a DPI device and may provide a metered nominal dose of 5 μg to 1000 μg of ensifentrine per inhalation. For example, the metered nominal dose per inhalation may be 10 μg to 500 μg.

[0038] Typically, the emitted dose from a DPI containing a dry powder pharmaceutical composition is 70%-95% of the metered nominal dose.

[0039] Typically, the dry powder pharmaceutical composition is administered to the patient via inhalation of a DPI 1 to 8 times per day. For example, the pharmaceutical composition may be administered to the patient via 1 or 2 inhalations up to 4 times per day.

[0040] The present invention provides a dry powder pharmaceutical composition as defined herein for use in a method for treating a disease or condition as defined herein, the method comprising inhaling (or actuating) a dry powder inhaler comprising the dry powder pharmaceutical composition, wherein the fine particle fraction of ensifentrine particles after inhalation (or actuation) is at least 20%. The fine particle fraction of ensifentrine particles after inhalation is typically at least 30%, preferably at least 35%. The fine particle fraction may be at least 40%.

[0041] Fine particle fraction (FPF) is the fraction of the emitted dose of ensifentrine particles having an aerodynamic diameter of less than 5 μm. The emitted dose is the total amount of ensifentrine particles emitted from a dry powder inhaler device containing the dry powder pharmaceutical composition.

[0042] The method of measuring fine particle fraction is well known to those skilled in the art.For example, FPF can be measured by cascade impaction technology such as Andersen Cascade Impactor or by Next Generation Impactor.Typically, the fine particle fraction of the dry powder formulation of ensifentrin is measured using Next Generation Impactor.

[0043] The present invention also provides a method of treating or preventing a disease or condition defined herein in a subject, the method comprising administering to said subject an effective amount of a dry powder pharmaceutical composition defined herein. The invention will now be described in more detail in the following examples. EXAMPLES

[0044] Working Example Materials and Methods The following raw materials were used: Micronized ensifentrin (Dv50: 1.3μm) Coarse lactose 1 (Dv50: 60μm) Coarse lactose 2 (Dv50: 75μm) Coarse lactose 3 (Dv50: 105μm) Fine lactose 1 (Dv50:<5μm) Fine lactose 2 (Dv50:<10μm) The particle size distribution of these raw materials is shown in Table 1.

[0045] [Table 1]

[0046] A dry powder composition was prepared by the following method. 1. Lactose grade was passed through a 450 μm sieve. 2. The total amount of fine and coarse lactose particles was weighed. 3. The lactose grade was added to the vessel of the high shear mixer and mixed for 5 minutes. 4. The total amount of ensifentrin was sieved and weighed. 5. Two-thirds of the lactose blend obtained in step 3 was removed. 6. The total amount of ensifentrine was added to the high shear mixer vessel, then one of the two-thirds of the lactose blend removed in step 5 was added to the composition. 7. The composition was mixed for 5 minutes. 8. The last of the two-thirds of the lactose grade blend removed in step 5 was added to the composition. 9. The composition was mixed for 5 minutes. 10. The resulting mixed dry powder composition was transferred to a polyethylene bag.

[0047] Example 1 – Formulation Comparison Formulations containing various lactose carriers and different amounts of ensifentrine were manufactured and filled into capsules for testing in a capsule dry powder inhaler. The formulations were evaluated for blend uniformity (percentage of label claim (%LC) and relative standard deviation (RSD)), content uniformity (%LC and RSD), and aerodynamic profile. The aerodynamic profile included measurements of non-emitted fraction, emitted dose (ED), fine particle dose (FPD), fine particle fraction (FPF), and mass balance.

[0048] First, three formulations were prepared containing coarse lactose 1 (Dv50: 60 μm), coarse lactose 2 (Dv50: 75 μm) and coarse lactose 3 (Dv50: 105 μm). The compositions (weight percent) and properties of these formulations are shown in Table 2.

[0049] [Table 2]

[0050] Formulation 1 containing coarse lactose 1 (Dv50: 60 μm) was found to have the highest FPF and ED, therefore coarse lactose 1 was selected as the preferred coarse lactose.

[0051] Next, formulations were made containing blends of coarse lactose 1 with either fine lactose 1 (Dv50<5 μm) or fine lactose 2 (Dv50<10 μm). The compositions and properties of these formulations are shown in Table 3.

[0052] [Table 3]

[0053] The addition of fine lactose 2 (Dv50<10 μm) was found to unexpectedly increase the FPF relative to the addition of fine lactose 1 (lower Dv50). Thus, the combination of coarse lactose 1 and fine lactose 2 was found to result in improved aerodynamic properties.

[0054] Compositions with different proportions of coarse lactose 1 (Dv50: 60 μm) and fine lactose (Dv50<10 μm) were then evaluated. The results are shown in Table 4.

[0055] [Table 4]

[0056] The addition of 3.75% by weight of fine lactose 2 was found to increase the FPF, but then when the proportion of fine lactose 2 was increased to 7.50% by weight, the FPF unexpectedly decreased. The analysis was repeated with a composition containing a higher proportion of ensifentrine (5% by weight). The results are shown in Table 5.

[0057] [Table 5]

[0058] The same pattern as for the formulation containing 0.25 wt% ensifentrine was observed for the formulation containing 5 wt% ensifentrine, with the highest FPF obtained when 3.75 wt% fine lactose 2 was used. When the proportion of fine lactose was increased to 7.50 wt%, the FPF decreased again.

[0059] Thus, it has been found that lactose blends containing reduced amounts (about 3.75% by weight) of fine lactose can be used to deliver increased FPF for dry powder compositions containing ensifentrine. The improved FPF is maintained for both the 0.25% by weight and 5% by weight ensifentrine compositions.

[0060] Example 2 – Stability assessment Formulations 12-14 of the present invention were prepared using the compositions shown in Table 6. Each blend formulation was filled into size #3 hypromellose capsules with a net fill weight of 20 mg / capsule.

[0061] [Table 6]

[0062] The stability of formulations 12, 13 and 14 was evaluated over a 24 month period at 25° C. and 60% RH. Each formulation was observed to remain stable over 24 months. No significant changes were observed in the assay or aerodynamic performance of the formulations.

[0063] The stability of formulations 12, 13, and 14 was also evaluated under accelerated conditions at 40° C. and 75% RH. Good stability was observed after storage under these conditions for at least 6 months.

[0064] Example 3 – Clinical Evaluation A two-part, 37-patient Phase II, single- and multiple-dose clinical trial with ensifentrine in patients with COPD was completed using DPI formulations 12, 13, and 14 (Table 6).

[0065] Single doses of ensifentrine up to 3 mg had a rapid, dose-dependent, and statistically significant bronchodilatory effect over 12 hours up to the 3 mg dose level. Ensifentrine doses of 0.15, 0.5, 1.5, and 3 mg provided a dose-dependent improvement from baseline in peak forced expiratory volume in 1 second (FEV1) up to 333 mL (over 4 hours) compared with placebo (p<0.01 for the 1.5 mg and 3 mg doses).

[0066] The second part of the study was a complete block crossover trial using the same patients dosed in the first part of the study. Ensifentrine doses of 0.15 mg to 3 mg administered twice daily for 7 days provided dose-dependent, highly statistically significant, and clinically meaningful improvements from baseline in day 7 peak FEV1 (over 4 hours) of 102, 175, 180, and 260 mL, respectively, compared with placebo (p ≤ 0.0001 for all dose groups). The improvements in FEV1 were sustained over the 12-hour dosing interval, as shown by clinically meaningful and statistically significant improvements in mean FEV1 over 12 hours to 147 mL (p < 0.05 for all dose groups), as well as day 7 morning trough FEV1 of 98, 87, and 97 mL, respectively (p ≤ 0.001 for each dose), compared with placebo.

Claims

1. (i) ensifentrin particles; (ii) coarse lactose particles having a Dv50 of 50 μm to 70 μm; and (iii) Fine lactose particles having a Dv50 of 5 μm to 10 μm 1. A dry powder pharmaceutical composition suitable for inhaled administration comprising: The fine lactose particles are present in an amount of 2.0% to 4.5% by weight based on the total weight of the dry powder pharmaceutical composition; A dry powder pharmaceutical composition, wherein the ensifentrine particles are present in an amount of 3.5% to 6.0% by weight, based on the total weight of the dry powder pharmaceutical composition.

2. 2. The dry powder pharmaceutical composition of claim 1, wherein the amount of fine lactose particles is from 3.5% to 4.0% by weight, based on the total weight of the dry powder pharmaceutical composition.

3. 2. The dry powder pharmaceutical composition of claim 1, wherein the coarse lactose particles have a Dv50 of 55 μm to 65 μm.

4. 2. The dry powder pharmaceutical composition of claim 1, wherein the ensifentrine particles comprise at least 90% by weight of ensifentrine or a pharma- ceutically acceptable salt thereof based on the total weight of the ensifentrine particles.

5. 5. The dry powder pharmaceutical composition of claim 4, wherein the ensifentrine particles comprise at least 95% by weight of ensifentrine or a pharma- ceutically acceptable salt thereof based on the total weight of the ensifentrine particles.

6. 2. The dry powder pharmaceutical composition of claim 1, wherein the ensifentrine particles have a Dv50 of 0.5 μm to 5.0 μm.

7. 7. The dry powder pharmaceutical composition of claim 6, wherein the ensifentrine particles have a Dv50 of 1.0 μm to 2.0 μm.

8. 2. The dry powder pharmaceutical composition of claim 1, wherein the total amount of ensifentrine particles, coarse lactose particles and fine lactose particles is at least 90.0% by weight, based on the total weight of the dry powder pharmaceutical composition.

9. 9. The dry powder pharmaceutical composition of claim 8, wherein the total amount of ensifentrine particles, coarse lactose particles and fine lactose particles is at least 95.0% by weight, based on the total weight of the dry powder pharmaceutical composition.

10. 10. The dry powder pharmaceutical composition of claim 1, wherein the dry powder pharmaceutical composition is suitable for administration by a dry powder inhaler.

11. A dry powder inhaler comprising the dry powder pharmaceutical composition of any one of claims 1 to 10.

12. A dry powder pharmaceutical composition according to any one of claims 1 to 10 for use in the treatment of the human or animal body.

13. 11. The dry powder pharmaceutical composition according to any one of claims 1 to 10 for use in the treatment or prevention of a disease or condition selected from asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, pulmonary fibrosis, pulmonary fibrosis, interstitial lung disease, skin disorders, atopic dermatitis, psoriasis, eye inflammation, cerebral ischemia, inflammatory diseases and autoimmune diseases.

14. 14. The dry powder pharmaceutical composition for use according to claim 13, wherein the disease or condition is chronic obstructive pulmonary disease (COPD).

15. A dry powder pharmaceutical composition according to any one of claims 1 to 10 for use in a method for treating a disease or condition as defined in claim 13, comprising The method comprises inhaling a dry powder inhaler containing a dry powder pharmaceutical composition; A dry powder pharmaceutical composition, wherein the fine particle fraction of ensifentrine particles after inhalation is at least 20%.

16. 16. The dry powder pharmaceutical composition for use according to claim 15, wherein the fine particle fraction of ensifentrine particles after inhalation is at least 30%.

17. 17. The dry powder pharmaceutical composition for use according to claim 16, wherein the fine particle fraction of ensifentrine particles after inhalation is at least 35%.

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