Method of preparing a composition and device for administering it

Abstract

This invention belongs to the pharmaceutical field, specifically relating to a composition, its preparation method, and a delivery device. The preparation method includes the step of mixing excipients with the active ingredient to prepare a mixture of raw materials and excipients. This preparation method is simple, time-efficient, and highly operable in production, and the resulting pharmaceutical composition improves the uniformity and stability of powder mixing.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a composition, its preparation method, delivery device, and uses. Background Technology

[0002] Dry powder inhalers (DPIs) are mainly used for targeted therapy of lung diseases such as asthma, chronic obstructive pulmonary disease, and lung infections. With the continuous affirmation of their clinical value, this technology has been developed into a drug delivery system that uses the lungs as the drug delivery environment to achieve systemic therapeutic effects, and has broad application prospects.

[0003] Among dry powder inhalers, combination formulations have shown superior symptom improvement compared to monotherapy. In recent years, the FDA has approved mainly combination products for inhaled drugs, but currently, monotherapy products are still the main products on the market in China. The market size of combination formulations is expected to gradually expand in the future.

[0004] The industrial production of dry powder inhalers faces many challenges, such as particle morphology and particle size distribution control of active ingredients and carrier particles, control and release of static electricity during powder processing, control of mixing uniformity, and stability during long-term storage.

[0005] The mixing process is a crucial step in the development of dry powder inhalers (DPIs) and one of the main challenges in DPI production. Because the active ingredient particles are typically smaller than 5 micrometers, they exhibit strong adhesion and electrostatic effects, resulting in extremely poor flowability and posing difficulties for pharmaceutical processing. Furthermore, the significant differences in particle size distribution and formulation amount between the active ingredient particles and the carrier particles necessitate high-intensity mixing to achieve homogeneity. This high mixing intensity inevitably affects the binding degree between the drug and the carrier and generates stronger electrostatic effects, potentially impacting the long-term stability of DPI formulations. Therefore, ensuring mixing uniformity and powder stability is a major challenge in the mixing process of dry powder inhalers.

[0006] Existing technical solutions have shortcomings in practical applications. For example, the technical solution disclosed in CN114425049A increases the content of fine particles after grinding with a ball mill, and its process is complex, making it unfeasible for industrial production; the technical solution disclosed in CN105412049A uses three-dimensional mixing, with a total mixing time of several hours, resulting in very low production efficiency. Summary of the Invention

[0007] Based on this, the present invention provides a composition, a method for preparing the same, and a drug delivery device. The preparation method of the composition provided by the present invention is simple, time-saving, and highly operable in production. The prepared composition can improve the uniformity and stability of powder mixing, while maintaining a high drug deposition rate in the lungs.

[0008] The present invention provides a method for preparing a composition, and a composition obtained by the method.

[0009] This invention uses volumetric diameter (VD) to represent particle size distribution. The term "D"... 50 "D" refers to the particle size at which the cumulative particle size distribution percentage reaches 50%. Physically, it means that 50% of the particles are larger than this diameter, and 50% are smaller. The term "D" is used in this context. 90 "" refers to the particle size at which the cumulative particle size distribution percentage reaches 90%. Its physical meaning is that particles larger than the specified particle size account for 10%, and particles smaller than the specified particle size account for 90%.

[0010] In this invention, "salt" refers to a pharmaceutically acceptable salt of the active ingredient, including acid addition salts, such as addition salts formed by the active ingredient with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, propionic acid, acetic acid, triphenylacetic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, malic acid, fumaric acid, and sine. For example, the salt is vilanterol triphenylacetic acid.

[0011] In this invention, "ester" refers to a pharmaceutically acceptable ester of the active ingredient, including, but not limited to, ester forms formed by the active ingredient with the following acids: furoic acid, propionic acid, acetic acid, and specifically, beclomethasone dipropionate, fluticasone propionate, fluticasone furoate, or mometasone furoate.

[0012] In this invention, the content of each formulation component of the composition is calculated based on the weight of the salt, ester, or hydrate of the excipient or active ingredient. If the excipient or active ingredient is not in the form of salt, ester, or hydrate, it is calculated based on the weight of the free form, such as "98.68% lactose monohydrate", "0.32% vilanterol triphenylacetic acid", "0.59% umembrymonium bromide", and "0.8% fluticasone furoate" as described in the embodiments of this invention.

[0013] In a first aspect, the present invention provides a method for preparing a composition comprising an active ingredient and excipients, the method comprising step 1: mixing the excipients with the active ingredient to prepare a mixture of raw materials and excipients;

[0014] The active ingredient is selected from at least one of the following: anticholinergic drugs, β2-receptor agonists, and glucocorticoids.

[0015] In some embodiments, the preparation method may further include step 2:

[0016] The raw material mixture from step 1 is mixed with the excipients in a three-dimensional manner to obtain the composition.

[0017] In some embodiments, the excipients and the active ingredients are mixed in a certain proportion in step 1.

[0018] In some embodiments, in step 1, the excipients and the active ingredients are mixed in a ratio of ≥5:1, preferably ≥7:1, more preferably 7:1 to 30:1, for example 7:1 or 10:1 or 13:1 or 16:1 or 19:1 or 22:1 or 25:1 or 27:1 or 30:1.

[0019] In some embodiments, the active ingredient is selected from at least one of the following: anticholinergic drugs, β2-receptor agonists, and glucocorticoids.

[0020] In some embodiments, the active ingredient is selected from anticholinergic drugs.

[0021] In some embodiments, the active ingredient is selected from β2-receptor agonists.

[0022] In some embodiments, the active ingredient is a glucocorticoid.

[0023] In some embodiments, the active ingredient is selected from at least one of the following: anticholinergic drugs and glucocorticoids.

[0024] In some embodiments, the active ingredient is selected from at least one of the following: β2-receptor agonists and glucocorticoids.

[0025] In some embodiments, the active ingredient is selected from at least one of the following: anticholinergic drugs and β2-receptor agonists.

[0026] In some embodiments, the anticholinergic drug includes, but is not limited to, one or more of tiotropium bromide, glycopyrronium bromide, umebromide, adecyl bromide, ipratropium bromide, oxybutynin chloride, and troxodium chloride, preferably umebromide or glycopyrronium bromide, more preferably umebromide.

[0027] In some embodiments, the β2-receptor agonist includes, but is not limited to, one or more of indacaterol or its salt, formoterol or its salt, vilanterol or its salt, salmeterol or its salt, olodaterol or its salt, preferably selected from vilanterol or its salt, or salmeterol or its salt, more preferably vilanterol triphenylacetate or salmeterol sinenamate, and most preferably vilanterol triphenylacetate.

[0028] In some embodiments, the glucocorticoid includes, but is not limited to, one or more of budesonide, mometasone or its esters, fluticasone or its esters, beclomethasone or its esters, preferably one or more of mometasone furoate, fluticasone furoate, fluticasone propionate, and beclomethasone dipropionate, more preferably fluticasone furoate or fluticasone propionate, and most preferably fluticasone furoate.

[0029] In some embodiments, the active ingredient is selected from at least one of the following: umebromide, vilanterol triphenylacetic acid, and fluticasone furoate.

[0030] In some embodiments, the active ingredient is fluticasone furoate.

[0031] In some embodiments, the active ingredient is selected from at least one of the following: umebromide, vilanterol triphenylacetic acid.

[0032] In some embodiments, the active ingredient is more preferably vilanterol triphenylacetic acid.

[0033] In some embodiments, the active ingredient is more preferably umebromide.

[0034] In some embodiments, the active ingredient is more preferably either umebromide or vilanterol triphenylacetic acid.

[0035] In some embodiments, the active ingredients are umebromide, vilanterol triphenylacetic acid, and fluticasone furoate.

[0036] In some embodiments, the active ingredient is selected from at least one of the following: umebromide and fluticasone furoate.

[0037] In some embodiments, the active ingredient is selected from at least one of the following: vilanterol triphenylacetic acid and fluticasone furoate.

[0038] In some implementations, the excipient includes lactose.

[0039] In some embodiments, the excipient may further include at least one selected from magnesium stearate, calcium stearate, or talc.

[0040] In some implementations, the excipients include lactose and magnesium stearate.

[0041] In some embodiments, the active ingredient is selected from at least one of the following: anticholinergic drugs and glucocorticoids, and the excipients include lactose.

[0042] In some embodiments, the active ingredient is selected from at least one of the following: anticholinergic drugs and β2-receptor agonists, and the excipients include lactose.

[0043] In some embodiments, the active ingredient is selected from at least one of the following: β2-receptor agonists and glucocorticoids, and the excipients include lactose.

[0044] In some embodiments, the active ingredient is selected from anticholinergic drugs, and the excipients include lactose.

[0045] In some embodiments, the active ingredient is selected from β2-receptor agonists, and the excipients include lactose.

[0046] In some embodiments, the active ingredient is a glucocorticoid, and the excipients include lactose.

[0047] In some embodiments, the active ingredient is selected from at least one of the following: anticholinergic drugs and glucocorticoids, and the excipients include lactose and magnesium stearate.

[0048] In some embodiments, the active ingredient is selected from at least one of the following: anticholinergic drugs and β2-receptor agonists, and the excipients include lactose and magnesium stearate.

[0049] In some embodiments, the active ingredient is selected from at least one of the following: β2-receptor agonists and glucocorticoids, and the excipients include lactose and magnesium stearate.

[0050] In some embodiments, the active ingredient is selected from anticholinergic drugs, and the excipients include lactose and magnesium stearate.

[0051] In some embodiments, the active ingredient is selected from β2-receptor agonists, and the excipients include lactose and magnesium stearate.

[0052] In some embodiments, the active ingredient is a glucocorticoid, and the excipients include lactose and magnesium stearate.

[0053] In some embodiments, the active ingredient is selected from at least one of the following: umebromide and fluticasone furoate, and the excipients include lactose.

[0054] In some embodiments, the active ingredient is selected from at least one of the following: umebromide and vilanterol triphenylacetic acid, and the excipients include lactose.

[0055] In some embodiments, the active ingredient is selected from at least one of the following: vilanterol triphenylacetic acid and fluticasone furoate, and the excipients include lactose.

[0056] In some embodiments, the active ingredient is selected from umebromide, and the excipients include lactose.

[0057] In some embodiments, the active ingredient is selected from vilanterol triphenylacetic acid, and the excipients include lactose.

[0058] In some embodiments, the active ingredient is fluticasone furoate, and the excipients include lactose.

[0059] In some embodiments, the active ingredient is selected from at least one of the following: umebromide and fluticasone furoate, and the excipients include lactose and magnesium stearate.

[0060] In some embodiments, the active ingredient is selected from at least one of the following: umebromide and vilanterol triphenylacetic acid, and the excipients include lactose and magnesium stearate.

[0061] In some embodiments, the active ingredient is selected from at least one of the following: vilanterol triphenylacetic acid and fluticasone furoate, and the excipients include lactose and magnesium stearate.

[0062] In some embodiments, the active ingredient is selected from umebromide, and the excipients include lactose and magnesium stearate.

[0063] In some embodiments, the active ingredient is selected from vilanterol triphenylacetic acid, and the excipients include lactose and magnesium stearate.

[0064] In some embodiments, the active ingredient is fluticasone furoate, and the excipients include lactose and magnesium stearate.

[0065] In some embodiments, the active ingredient is present in a weight percentage of 0.01% to 10%.

[0066] In some embodiments, the excipients have a mass percentage of ≥90%, preferably 90% to 99.99%.

[0067] In some embodiments, the active ingredient comprises 0.01% to 10% by weight, and the excipients comprise 90% to 99.99% by weight.

[0068] In some embodiments, the lactose comprises 90% to 99.99% by weight, and the glucocorticoid comprises 0.01% to 10% by weight.

[0069] In some embodiments, the lactose monohydrate is 90% to 99.99% by weight, and the glucocorticoid is 0.01% to 10% by weight.

[0070] In some embodiments, the lactose monohydrate is 98% to 99.9% by weight, and the glucocorticoid is 0.01% to 2% by weight.

[0071] In some embodiments, the lactose is selected from at least one of lactose monohydrate or anhydrous lactose.

[0072] In some embodiments, the excipients include lactose monohydrate and magnesium stearate.

[0073] In some embodiments, the lactose monohydrate has a mass percentage of ≥90%, the magnesium stearate has a mass percentage of 0-5%, and the remaining mass percentage is the active ingredient.

[0074] In some embodiments, the lactose monohydrate has a mass percentage of ≥90%, the magnesium stearate has a mass percentage of 0.01 to 5%, and the remaining mass percentage is the active ingredient.

[0075] In some embodiments, the lactose monohydrate comprises 90-99.8% by mass, the magnesium stearate comprises 0.01-5% by mass, and the remaining mass percentage is the active ingredient.

[0076] In some embodiments, the lactose monohydrate comprises 94-99.5% by mass, the magnesium stearate comprises 0.1-5% by mass, and the remaining mass percentage is the active ingredient.

[0077] In some embodiments, the lactose monohydrate comprises 94-99.5% by mass, the magnesium stearate comprises 0.1-1.5% by mass, and the remaining mass percentage is the active ingredient.

[0078] In some embodiments, the lactose monohydrate is 97-99% by mass, for example 98-99%.

[0079] In some embodiments, the magnesium stearate is present in a mass percentage of 0.4% to 1.5%, for example, 0.4%, 0.6%, 0.8%, or 1%.

[0080] In some embodiments, the active ingredient or the excipient is in a micronized state.

[0081] In some embodiments, the particle size distribution of the active ingredient is D. 50 ≤4.5μm.

[0082] In some embodiments, the active ingredient has a particle size distribution of 0.1 μm ≤ D. 50 ≤4.5μm.

[0083] In some embodiments, the active ingredient has a particle size distribution of D. 50≤4.5μm, the active ingredient is preferably selected from at least one of the following: umebromide, vilanterol triphenylacetic acid.

[0084] In some embodiments, the active ingredient has a particle size distribution of 0.1 μm ≤ D. 50 ≤4.5μm, the active ingredient is preferably selected from at least one of the following: umebromide, vilanterol triphenylacetic acid.

[0085] In some embodiments, the particle size distribution of the excipient is D. 90 ≤200μm, preferably 1μm≤D 90 ≤200μm, more preferably 1μm≤D 90 ≤50μm.

[0086] In some embodiments, the particle size distribution of the lactose monohydrate is D. 90 ≤200μm.

[0087] In some embodiments, the particle size distribution of the lactose monohydrate is 1 μm ≤ D 90 ≤200μm.

[0088] In some embodiments, the particle size distribution of the magnesium stearate is D. 90 ≤50μm.

[0089] In some embodiments, the magnesium stearate has a particle size distribution of 1 μm ≤ D. 90 ≤50μm.

[0090] In some implementations, when the excipients are of multiple types, such as two or more, the excipients may also include a mixing step.

[0091] In some implementations, the excipients may be divided into multiple portions, such as 1 portion, 2 portions, or 3 portions, and mixed with the raw and excipient mixture in step 1.

[0092] In some implementations, the mixing is selected from high-shear mixing and three-dimensional mixing.

[0093] In some implementations, the mixing is a three-dimensional mixing.

[0094] In some implementations, the rotational speed of the three-dimensional mixing is ≥10 rpm, preferably ≥15 rpm.

[0095] In some embodiments, the rotational speed of the three-dimensional mixing includes, but is not limited to, 10 rpm, 11 rpm, 12 rpm, 13 rpm, 14 rpm, 15 rpm, 16 rpm, 17 rpm, 18 rpm, 19 rpm, 20 rpm, 21 rpm, 22 rpm, 23 rpm, 24 rpm, 25 rpm, 26 rpm, 27 rpm, 28 rpm, 29 rpm, 30 rpm, 31 rpm, 32 rpm, 33 rpm, 34 rpm, 35 rpm, 36 rpm, 37 rpm, 38 rpm, 39 rpm, 40 rpm, 41 rpm, 42 rpm, 43 rpm, 44 rpm, 45 rpm, 46 rpm, 47 rpm, 48 rpm, 49 rpm, 50 rpm, 51 rpm, 52 rpm, 53 rpm, 54 rpm, 55 rpm, 56 rpm, 57 rpm, 58 rpm, 59 rpm, 60 rpm, or a range between any two of the foregoing.

[0096] In some embodiments, the rotational speed of the three-dimensional mixing is more preferably 15 to 60 rpm, and most preferably 15 to 45 rpm or 20 to 40 rpm, for example 20 rpm or 25 rpm or 30 rpm or 35 rpm or 40 rpm.

[0097] In some implementations, the mixing time for the three-dimensional mixing is ≥10 min.

[0098] In some implementations, the mixing time for the three-dimensional mixing includes, but is not limited to, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 21 min, 22 min, 23 min, 24 min, 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 31 min, 32 min, 33 min, 34 min, 35 min, 36 min, 37 min, 38 min, 39 min, 40 min, 41 min, 42 min, 43 min, 44 min, 45 min, 46 min, 47 min, 48 min, 49 min, 50 min, 51 min, 52 min, 53 min, 54 min, 55 min, 56 min, 57 min, 58 min, 59 min, 60 min, or a range prior to any two of the foregoing.

[0099] In some embodiments, the mixing time for the three-dimensional mixing is preferably 10 to 60 minutes, more preferably 10 to 50 minutes, and most preferably 15 to 45 minutes, for example 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, or 45 minutes.

[0100] In some implementations, the three-dimensional mixing speed is ≥15 rpm and the mixing time is ≥10 min.

[0101] In some implementations, the rotational speed of the three-dimensional mixing is 15–60 rpm, and the mixing time is 10–60 min.

[0102] In some implementations, the three-dimensional mixing speed is 15–60 rpm and the mixing time is 10–50 min.

[0103] In some implementations, the rotational speed of the three-dimensional mixing is 15–60 rpm, and the mixing time is 15–45 min.

[0104] In some implementations, the three-dimensional mixing speed is 15–45 rpm and the mixing time is 10–60 min.

[0105] In some implementations, the rotational speed of the three-dimensional mixing is 15–45 rpm, and the mixing time is 10–50 min.

[0106] In some implementations, the three-dimensional mixing speed is 15–45 rpm and the mixing time is 15–45 min.

[0107] In some implementations, the three-dimensional mixing speed is 20-40 rpm and the mixing time is 10-60 min.

[0108] In some implementations, the three-dimensional mixing speed is 20-40 rpm and the mixing time is 10-50 min.

[0109] In some implementations, the three-dimensional mixing speed is 20-40 rpm and the mixing time is 15-45 min.

[0110] In some implementations, the mixing is a high-shear mixing.

[0111] In some embodiments, the high-shear mixing speed is 200–900 rpm.

[0112] In some embodiments, the high-shear mixing speed is preferably 300 to 800 rpm.

[0113] In some embodiments, the high-shear mixing speed includes, but is not limited to, 300 rpm, 325 rpm, 350 rpm, 375 rpm, 400 rpm, 425 rpm, 450 rpm, 475 rpm, 500 rpm, 525 rpm, 550 rpm, 575 rpm, 600 rpm, 625 rpm, 650 rpm, 675 rpm, 700 rpm, 725 rpm, 750 rpm, 800 rpm, or a range between any two of the foregoing.

[0114] In some embodiments, the high-shear mixing speed is more preferably 350-700 rpm, and most preferably 600-700 rpm, 300-450 rpm, or 300-400 rpm, for example 700 rpm, 650 rpm, 450 rpm, 400 rpm, or 350 rpm.

[0115] In some implementations, the mixing time for the high-shear mixing is 3 to 20 minutes.

[0116] In some embodiments, the mixing time of the high-shear mixing includes, but is not limited to, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, or any range between the two.

[0117] In some embodiments, the mixing time for the high-shear mixing is preferably 4 to 15 minutes, more preferably 5 to 10 minutes.

[0118] In some embodiments, the mixing time for the high-shear mixing is preferably 7 to 10 minutes or 4 to 6 minutes, for example 10 minutes or 8.5 minutes or 7.5 minutes or 6 minutes or 5 minutes.

[0119] In some embodiments, the high-shear mixing speed is 350–700 rpm and the mixing time is 5–10 min.

[0120] In some embodiments, the high-shear mixing speed is 600-700 rpm and the mixing time is 7-10 min.

[0121] In some embodiments, the high-shear mixing speed is 300-450 rpm and the mixing time is 7-10 min.

[0122] In some embodiments, the high-shear mixing speed is 600-700 rpm and the mixing time is 4-6 min.

[0123] In some embodiments, the high-shear mixing speed is 300-450 rpm and the mixing time is 4-6 min.

[0124] In some embodiments, the high-shear mixing speed is 300-400 rpm and the mixing time is 7-10 min.

[0125] In some embodiments, the high-shear mixing speed is 300-400 rpm and the mixing time is 4-6 min.

[0126] In some embodiments, step 1 further includes sieving after mixing in step 1, and the mesh size of the sieve is ≥24 mesh, preferably 24 mesh to 60 mesh, for example 24 mesh, 30 mesh, 40 mesh or 60 mesh.

[0127] In some embodiments, the excipients and active ingredients are mixed in a ratio of ≥5:1 and then sieved, preferably ≥7:1, more preferably 7:1 to 30:1, for example 7:1 or 10:1 or 13:1 or 16:1 or 19:1 or 22:1 or 25:1 or 27:1 or 30:1.

[0128] In some implementations, the active ingredient and / or the excipients may be sieved before use.

[0129] In some embodiments, the excipient (e.g., lactose, or lactose monohydrate) is sieved before use with a sieve mesh of 20 to 100 mesh, preferably 40 mesh.

[0130] In some embodiments, the active ingredient (e.g., fluticasone furoate, umebromide, or vilanterol triphenylacetic acid) is sieved before use with a sieve mesh of 20 to 100 mesh, preferably 24 mesh.

[0131] In some implementations, the rotational speed of the three-dimensional mixing in step 2 is ≥10 rpm, preferably ≥15 rpm.

[0132] In some embodiments, the rotational speed for the three-dimensional mixing in step 2 includes, but is not limited to, 10 rpm, 11 rpm, 12 rpm, 13 rpm, 14 rpm, 15 rpm, 16 rpm, 17 rpm, 18 rpm, 19 rpm, 20 rpm, 21 rpm, 22 rpm, 23 rpm, 24 rpm, 25 rpm, 26 rpm, 27 rpm, 28 rpm, 29 rpm, 30 rpm, 31 rpm, 32 rpm, 33 rpm, 34 rpm, 35 rpm, 36 rpm, 37 rpm, 38 rpm, 39 rpm, 40 rpm, 41 rpm, 42 rpm, 43 rpm, 44 rpm, 45 rpm, 46 rpm, 47 rpm, 48 rpm, 49 rpm, 50 rpm, 51 rpm, 52 rpm, 53 rpm, 54 rpm, 55 rpm, 56 rpm, 57 rpm, 58 rpm, 59 rpm, 60 rpm, or a range between any two of the foregoing.

[0133] In some embodiments, the rotational speed of the three-dimensional mixing in step 2 is more preferably 15-60 rpm, and most preferably 15-45 rpm or 20-40 rpm, for example 20 rpm or 25 rpm or 30 rpm or 35 rpm or 40 rpm.

[0134] In some implementations, the mixing time for the three-dimensional mixing in step 2 is ≥10 min.

[0135] In some implementations, the mixing time for the three-dimensional mixing in step 2 includes, but is not limited to, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 21 min, 22 min, 23 min, 24 min, 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 31 min, 32 min, 33 min, 34 min, 35 min, 36 min, 37 min, 38 min, 39 min, 40 min, 41 min, 42 min, 43 min, 44 min, 45 min, 46 min, 47 min, 48 min, 49 min, 50 min, 51 min, 52 min, 53 min, 54 min, 55 min, 56 min, 57 min, 58 min, 59 min, 60 min, or a range prior to any two of the foregoing.

[0136] In some embodiments, the mixing time for the three-dimensional mixing in step 2 is preferably 10 to 60 minutes, more preferably 10 to 50 minutes, and most preferably 15 to 45 minutes, for example 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, or 45 minutes.

[0137] In some implementations, the rotational speed of the three-dimensional mixing in step 2 is ≥15 rpm and the mixing time is ≥10 min.

[0138] In some implementations, the rotation speed of the three-dimensional mixing in step 2 is 15-60 rpm, and the mixing time is 10-60 min.

[0139] In some implementations, the rotation speed of the three-dimensional mixing in step 2 is 15-60 rpm, and the mixing time is 10-50 min.

[0140] In some implementations, the rotation speed of the three-dimensional mixing in step 2 is 15-60 rpm, and the mixing time is 15-45 min.

[0141] In some implementations, the rotation speed of the three-dimensional mixing in step 2 is 15-45 rpm, and the mixing time is 10-60 min.

[0142] In some implementations, the rotation speed of the three-dimensional mixing in step 2 is 15-45 rpm, and the mixing time is 10-50 min.

[0143] In some implementations, the rotation speed of the three-dimensional mixing in step 2 is 15-45 rpm, and the mixing time is 15-45 min.

[0144] In some implementations, the rotation speed of the three-dimensional mixing in step 2 is 20-40 rpm, and the mixing time is 10-60 min.

[0145] In some implementations, the rotation speed of the three-dimensional mixing in step 2 is 20-40 rpm, and the mixing time is 10-50 min.

[0146] In some implementations, the rotation speed of the three-dimensional mixing in step 2 is 20-40 rpm, and the mixing time is 15-45 min.

[0147] In some embodiments, the composition in the preparation method described above is a dry powder composition.

[0148] In some embodiments, the dry powder composition comprises vilanterol triphenylacetic acid and excipients.

[0149] In some embodiments, the dry powder composition comprises umelemonamine bromide and excipients.

[0150] In some embodiments, the dry powder composition comprises fluticasone furoate and excipients.

[0151] In some embodiments, the dry powder composition is a dry powder composition comprising umebromide, vilanterol triphenylacetic acid, and excipients.

[0152] In some embodiments, the dry powder composition is a dry powder composition comprising umebromide, vilanterol triphenylacetic acid, fluticasone furoate, and excipients.

[0153] In some embodiments, the composition in the preparation method described above is a dry powder inhalation composition.

[0154] In some embodiments, the dry powder inhalation composition comprises vilanterol triphenylacetic acid and excipients.

[0155] In some embodiments, the dry powder inhalation composition comprises umebromide and excipients.

[0156] In some embodiments, the dry powder inhalation composition comprises fluticasone furoate and excipients.

[0157] In some embodiments, the dry powder inhalation composition is a dry powder composition comprising umebromide, vilanterol triphenylacetic acid, and excipients.

[0158] In some embodiments, the dry powder inhalation composition is a dry powder composition comprising umebromide, vilanterol triphenylacetic acid, fluticasone furoate, and excipients.

[0159] In some embodiments, the active ingredients in the composition may be provided as individually packaged components or as a mixture.

[0160] In some implementations, the active ingredients are combined in the form of individually packaged products.

[0161] In some embodiments, the active ingredients are combined in individually packaged forms, and each composition is prepared independently according to the preparation method described in this invention.

[0162] In some embodiments, the active ingredients are combined in individually packaged form, and the compositions include compositions containing umebromide and excipients, and compositions containing vilanterol triphenylacetic acid and excipients.

[0163] In some embodiments, the active ingredients are combined in individually packaged forms, and the pharmaceutical composition includes a composition comprising umebromide and excipients and a composition comprising vilanterol triphenylacetate and excipients, wherein the umebromide and excipient composition and the vilanterol triphenylacetate and excipient composition are each prepared independently according to the preparation method.

[0164] In some embodiments, the active ingredients are combined in individually packaged form, and the compositions include compositions containing umebromide and excipients and compositions containing fluticasone furoate and excipients.

[0165] In some embodiments, the active ingredients are combined in separate packages, and the pharmaceutical composition comprises a composition containing umebromide and excipients and a composition containing fluticasone furoate and excipients, wherein the composition containing umebromide and excipients and the composition containing fluticasone furoate and excipients are each prepared independently according to the preparation method.

[0166] In some embodiments, the active ingredients are combined in separate packages, and the compositions include compositions containing vilanterol triphenylacetic acid and excipients, and compositions containing fluticasone furoate and excipients.

[0167] In some embodiments, the active ingredients are combined in individually packaged forms, and the pharmaceutical composition comprises a composition containing vilanterol triphenylacetate and excipients and a composition containing fluticasone furoate and excipients, wherein the composition containing vilanterol triphenylacetate and excipients and the composition containing fluticasone furoate and excipients are each prepared independently according to the preparation method.

[0168] In some embodiments, the active ingredients are combined in individually packaged forms, and the compositions include compositions containing umebromide and excipients, compositions containing vilanterol triphenylacetic acid and excipients, and compositions containing fluticasone furoate and excipients.

[0169] In some embodiments, the active ingredients are combined in individually packaged forms, and the pharmaceutical composition includes a composition containing umebromide and excipients, a composition containing vilanterol triphenylacetate and excipients, and a composition containing fluticasone furoate and excipients, wherein the compositions containing umebromide and excipients, the compositions containing vilanterol triphenylacetate and excipients, and the compositions containing fluticasone furoate and excipients are each prepared independently according to the preparation method.

[0170] In some embodiments, the active ingredients are mixed as a mixture, the composition is prepared according to the preparation method, and the composition is in the form of a separately packaged composition.

[0171] In a second aspect of the present invention, the compositions, dry powder compositions, or dry powder inhalation compositions provided by the present invention are prepared by the preparation method provided in the first aspect of the present invention.

[0172] In a third aspect, the present invention provides a drug delivery device comprising the composition of the second aspect, a dry powder composition, or a dry powder inhalation composition.

[0173] In some embodiments, the composition, dry powder composition, or dry powder inhalation composition contained in the drug delivery device may be present in the drug delivery device in the form of a capsule, cartridge, or blister pack, for example, in the form of an aluminum foil blister pack strip.

[0174] In a fourth aspect, the use of the composition (e.g., a dry powder composition or a dry powder inhalation composition) and the delivery device of the first aspect provided by the present invention in the preparation of a medicament for treating or preventing inflammatory diseases or respiratory diseases, including pulmonary infectious diseases, and including but not limited to chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, allergic rhinitis, bronchiectasis, and cystic fibrosis.

[0175] The compositions of the present invention (e.g., dry powder compositions or dry powder inhalation compositions) are obtained by mixing active ingredients and excipients of suitable particle size at appropriate speeds and mixing methods. Sieving the mixture of active ingredients and excipients after mixing reduces the loss and agglomeration of active ingredients, while avoiding the generation of large amounts of static electricity. This method is highly operable and can prepare a uniform and stable powder system in a shorter time, significantly improving production efficiency compared to existing methods. Furthermore, the prepared compositions (e.g., dry powder compositions or dry powder inhalation compositions) exhibit high lung deposition rates and product stability. They offer advantages such as simple preparation processes, ease of commercial production, and increased lung deposition of active ingredients. The quality indicators of the aforementioned compositions (e.g., dry powder compositions or dry powder inhalation compositions) are comparable to those of commercially available products, making them suitable for treating respiratory diseases such as asthma and chronic obstructive pulmonary disease, with broad application prospects. Detailed Implementation

[0176] The compositions (e.g., dry powder compositions or dry powder inhalation compositions) of the present invention, their preparation methods, and delivery devices are described in further detail below with reference to specific embodiments. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0177] Unless otherwise specified, the temperature parameters in this invention can be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows temperature fluctuations within the precision range controlled by the instrument.

[0178] In this invention, RSD (Relative Standard Deviation) is the RSD value of the active ingredient content measured by sampling from 10 different parts of the composition that best represent the mixing uniformity. The results are expressed as a percentage, where an RSD value ≤ 3.0% indicates good mixing uniformity and > 3.0% indicates poor mixing uniformity.

[0179] In this invention, the term "aerodynamic particle size distribution (APSD)" refers to the quantity or mass distribution of particles within different particle size ranges. It reflects the distribution of particle size.

[0180] In this invention, the term "fine particle dose (FPD)" refers to the dose of D in all levels of the NGI. 50 The dosage of active ingredients with a value less than 5 μm, expressed in μg, can be calculated from APSD data using professional software included with the equipment from the UK company COPLEY.

[0181] In this invention, the term "fine particle dose percentage (FPF)" refers to the percentage of fine particle dose (FPD) relative to the total number of collected particles, which can be calculated from APSD data using professional software included with the equipment from Copley Ltd. in the UK.

[0182] In this invention, the term "MMAD" refers to the mass median aerodynamic particle size, which represents the median particle size and can be calculated from APSD data using professional software provided with the equipment from the British company Copley.

[0183] In this invention, "the fine particle dose and fine particle dose percentage of each active ingredient are no worse than those of commercially available products" means that the fine particle dose and fine particle dose percentage of each active ingredient are no less than 15% of those of commercially available products.

[0184] In this invention, the commercially available product 1 is fluticasone furoate and vilanterol inhalation powder (II) from GlaxoSmithKline plc (GSK), with a specification of 100 μg / 25 μg (calculated as fluticasone furoate and vilanterol, respectively).

[0185] In this invention, the commercially available product 2 is GlaxoSmithKline plc (GSK) umemetammonium vilanterol inhalation powder, with a specification of 62.5 μg / 25 μg (calculated as umemetammonium and vilanterol, respectively).

[0186] In this invention, the commercially available product 3 is fluticasone furoate, umeclidinium, and vilanterol inhalation powder from GlaxoSmithKline plc (GSK), with specifications of 100μg / 62.5μg / 25μg (calculated as fluticasone furoate, umeclidinium, and vilanterol, respectively).

[0187] The raw materials and reagents involved in the following specific embodiments can be obtained commercially or prepared by those skilled in the art using known methods.

[0188] The 3D mixer is a TURBULA type 3D mixing equipment (17L tank) purchased from WAB.

[0189] The high-shear mixer is a TRV mixing unit (20L pot) purchased from GEA GmbH, Germany.

[0190] The new generation impactor (NGI) was purchased from the British company Copley.

[0191] Example 1 Fluticasone furoate dry powder inhalation composition

[0192] Example 1-1

[0193] (i) Formulation and material processing: 99.2% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.8% micronized fluticasone furoate, passed through a 24-mesh sieve for later use;

[0194] (ii) Preparation method of the composition: lactose monohydrate and micronized fluticasone furoate were placed in a three-dimensional mixer and mixed at 40 rpm for 45 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 1.

[0195] Examples 1-2

[0196] (i) Formulation and material processing: 99.2% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.8% micronized fluticasone furoate, passed through a 24-mesh sieve for later use;

[0197] (ii) Preparation method of the composition: lactose monohydrate and micronized fluticasone furoate were placed in a three-dimensional mixer and mixed at 30 rpm for 30 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 1.

[0198] Examples 1-3

[0199] (i) Formulation and material processing: 99.2% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.8% micronized fluticasone furoate, passed through a 24-mesh sieve for later use;

[0200] (ii) Preparation method of the composition: lactose monohydrate and micronized fluticasone furoate were placed in a three-dimensional mixer and mixed at 20 rpm for 15 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 1.

[0201] Table 1. Content results of the dry powder inhalation compositions in Examples 1-1 to 1-3

[0202]

[0203] The mixing uniformity of Examples 1-1 to 1-3 was good (RSD value less than 2%), with Example 1-1 showing the best uniformity. Because this product is produced in small quantities, the risk of content uniformity is high. The dry powder inhalation compositions of the present invention (e.g., Examples 1-1 to 1-3) help reduce the risk of content uniformity and delivery dose uniformity in the final product.

[0204] Example 2: Triphenylacetic acid vilanterol dry powder inhalation composition

[0205] Example 2-1

[0206] (i) Formulation and material handling: 98.68% lactose monohydrate, passed through a 40-mesh sieve for later use; 1% magnesium stearate; 0.32% micronized vilanterol triphenylacetic acid;

[0207] (ii) High shear mixing: The lactose and magnesium stearate from step (i) are placed in a high shear mixer and mixed at 700 rpm for 10 minutes to obtain the excipient mixture;

[0208] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the micronized triphenylacetic acid vilanterol from step (i) at a ratio of 7:1 and then passed through a 60-mesh sieve to obtain the excipient mixture.

[0209] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 40 rpm for 45 minutes to obtain the dry powder inhalation composition. The content and mixing uniformity results are shown in Table 2.

[0210] Example 2-2

[0211] (i) Formulation and material handling: 98.68% lactose monohydrate, passed through a 40-mesh sieve for later use; 1% magnesium stearate; 0.32% micronized vilanterol triphenylacetic acid;

[0212] (ii) High shear mixing: The lactose and magnesium stearate from step (i) were placed in a high shear mixer and mixed at 600 rpm for 7.5 minutes to obtain the excipient mixture;

[0213] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the micronized triphenylacetic acid vilanterol from step (i) at a ratio of 7:1 and then passed through a 60-mesh sieve to obtain the excipient mixture.

[0214] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 30 rpm for 30 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 2.

[0215] Example 2-3

[0216] (i) Formulation and material handling: 98.68% lactose monohydrate, passed through a 40-mesh sieve for later use; 1% magnesium stearate; 0.32% micronized vilanterol triphenylacetic acid;

[0217] (ii) High shear mixing: The lactose and magnesium stearate from step (i) are placed in a high shear mixer and mixed at 350 rpm for 5 minutes to obtain an excipient mixture;

[0218] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the micronized triphenylacetic acid vilanterol from step (i) at a ratio of 7:1 and then passed through a 60-mesh sieve to obtain the excipient mixture.

[0219] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 20 rpm for 15 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 2.

[0220] Table 2. Content results of the dry powder inhalation compositions in Examples 2-1 to 2-3

[0221]

[0222] Examples 2-1 to 2-3 exhibited good mixing uniformity (RSD value less than 3%), with Example 2-1 showing the best uniformity. Due to the small size of this product, the risk of content uniformity is relatively high. The dry powder inhalation compositions of the present invention (e.g., Examples 2-1 to 2-3) help reduce the risk of final product content uniformity and delivery dose uniformity.

[0223] Example 3 Umeprazole dry powder inhalation composition

[0224] Example 3-1

[0225] (i) Formulation and material processing: 98.81% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.60% magnesium stearate; 0.59% micronized umelemonamine bromide;

[0226] (ii) High shear mixing: The lactose and magnesium stearate from step (i) are placed in a high shear mixer and mixed at 700 rpm for 10 minutes to obtain the excipient mixture;

[0227] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) and the micronized umelemonamine bromide from step (i) are mixed in a 7:1 ratio and then passed through a 60-mesh sieve to obtain the raw material and excipient mixture.

[0228] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 40 rpm for 45 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 3.

[0229] Example 3-2

[0230] (i) Formulation and material processing: 98.81% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.60% magnesium stearate; 0.59% micronized umelemonamine bromide;

[0231] (ii) High shear mixing: The lactose and magnesium stearate from step (i) were placed in a high shear mixer and mixed at 600 rpm for 7.5 minutes to obtain the excipient mixture;

[0232] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) and the micronized umelemonamine bromide from step (i) are mixed in a 7:1 ratio and then passed through a 60-mesh sieve to obtain the raw material and excipient mixture.

[0233] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 30 rpm for 30 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 3.

[0234] Example 3-3

[0235] (i) Formulation and material processing: 98.81% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.60% magnesium stearate; 0.59% micronized umelemonamine bromide;

[0236] (ii) High shear mixing: The lactose and magnesium stearate from step (i) are placed in a high shear mixer and mixed at 350 rpm for 5 minutes to obtain the excipient mixture;

[0237] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) and the micronized umelemonamine bromide from step (i) are mixed in a 7:1 ratio and then passed through a 60-mesh sieve to obtain the raw material and excipient mixture.

[0238] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 20 rpm for 15 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 3.

[0239] Table 3. Content results of the dry powder inhalation compositions in Examples 3-1 to 3-3

[0240]

[0241] Examples 3-1 to 3-3 exhibited good mixing uniformity (RSD value less than 3%), with Example 3-1 showing the best uniformity. Due to the small size of this product, the risk of content uniformity is high. The dry powder inhalation compositions of this invention (e.g., Examples 3-1 to 3-3) help reduce the risk of final product content uniformity and delivery dose uniformity.

[0242] Example 4: Umeprazole and vilanterol dry powder inhalation composition

[0243] Example 4-1

[0244] (i) Formulation and material processing: 98.49% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.60% magnesium stearate; 0.59% micronized umebromide; 0.32% micronized vilanterol triphenylacetic acid;

[0245] (ii) High shear mixing: The lactose and magnesium stearate from step (i) are placed in a high shear mixer and mixed at 700 rpm for 10 minutes to obtain the excipient mixture;

[0246] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the total amount of triphenylacetic acid vilanterol and micronized umebromide from step (i) in a ratio of 7:1 and then passed through a 60-mesh sieve to obtain the raw material and excipient mixture.

[0247] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 40 rpm for 45 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 4.

[0248] Example 4-2

[0249] (i) Formulation and material processing: 98.81% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.60% magnesium stearate; 0.59% micronized umebromide; 0.32% micronized vilanterol triphenylacetate;

[0250] (ii) High shear mixing: The lactose and magnesium stearate from step (i) were placed in a high shear mixer and mixed at 600 rpm for 7.5 minutes to obtain the excipient mixture;

[0251] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the total amount of triphenylacetic acid vilanterol and micronized umebromide from step (i) in a ratio of 7:1 and then passed through a 60-mesh sieve to obtain the raw material and excipient mixture.

[0252] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 30 rpm for 30 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 4.

[0253] Example 4-3

[0254] (i) Formulation and material processing: 98.81% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.60% magnesium stearate; 0.59% micronized umebromide; 0.32% micronized vilanterol triphenylacetate;

[0255] (ii) High shear mixing: The lactose and magnesium stearate from step (i) are placed in a high shear mixer and mixed at 350 rpm for 5 minutes to obtain an excipient mixture;

[0256] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the total amount of triphenylacetic acid vilanterol and micronized umebromide from step (i) in a ratio of 7:1 and then passed through a 60-mesh sieve to obtain the raw material and excipient mixture.

[0257] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 20 rpm for 15 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 4.

[0258] Table 4. Content results of the dry powder inhalation compositions in Examples 4-1 to 4-3

[0259]

[0260] Examples 4-1 to 4-3 exhibited good mixing uniformity (RSD values ​​less than 3%), with Example 4-1 showing the best uniformity. Due to the small size of this product, the risk of content uniformity is high. The dry powder inhalation compositions of this invention (e.g., Examples 4-1 to 4-4) help reduce the risk of content uniformity and delivery dose uniformity in the final product.

[0261] Example 5: Microparticle Dosing Measurement

[0262] The dosage of fine particles is an important parameter for evaluating the quality of inhaled formulations. The dry powder inhalation composition samples obtained in Examples 1-1 to 4-3 were filled using a blister packing device at a dosage of 12.5 mg / blister and 30 blister packs / strip. Two aluminum foil blister packs were coiled and inserted into specific inhalation devices to obtain dry powder inhalation compositions. Examples of the numbered and corresponding compositions are shown in Table 5.

[0263] Table 5. Composition details for dry powder inhalation compositions.

[0264]

[0265]

[0266] Using a new generation impactor (NGI), the aerodynamic particle size distribution (APSD) of the above-mentioned dry powder inhalation composition and commercially available products was measured at a flow rate of 60 L / min, and the fine particle dose results were calculated using professional software and are shown in Tables 6-8.

[0267] Table 6. Dosage results of fine particles in dry powder inhalation compositions 1-3

[0268]

[0269] Table 7. Dosage results of fine particles in dry powder inhalation compositions 4-6

[0270]

[0271] Table 8. Dosage results of fine particles 7-9 in dry powder inhalation compositions.

[0272]

[0273] The data in the table above show that the fine particle dose (FPD) and fine particle dose percentage (FPF) of each active ingredient in samples 1-9 prepared by the method of this invention are no worse than those of commercially available products. However, the fine particle dose (FPD) and fine particle dose percentage (FPF) of each active ingredient in samples 3, 6, and 9 are close to the values ​​of commercially available products, indicating that mixing parameters below the scope of this invention pose a risk that the fine particle dose (FPD) and fine particle dose percentage (FPF) will be lower than those of commercially available products.

[0274] Example 6: Stability Study of Dry Powder Inhalation Composition

[0275] In this embodiment, the stability of the dry powder inhalation composition prepared by the method of the present invention was investigated for 8 weeks. The dry powder inhalation compositions prepared in Examples 1-2, 2-2, 3-2, and 4-2 were placed at an environment not exceeding 25°C for 56 days, and the composition content was detected from 10 representative sites. The specific data are shown in Table 9.

[0276] Table 9. Content results of dry powder inhalation compositions at 0, 5, and 6 days.

[0277]

[0278]

[0279] The data in the table above show that the dry powder inhalation composition prepared by the method of the present invention can maintain stable content and mixing uniformity (RSD value) after being stored at an environment not higher than 25°C for 56 days.

[0280] The dry powder inhalation compositions prepared in Examples 1-2, 2-2, 3-2, and 4-2 were filled and assembled according to Table 10 on the 56th day of storage to obtain samples 10 and 11. The aerodynamic particle size distribution (APSD) of the assembled samples was measured at a flow rate of 60 L / min, and the fine particle dose results were calculated using professional software. The specific data are shown in Table 11.

[0281] Table 10 Assembly List of Stability Samples for Dry Powder Inhalation Compositions

[0282]

[0283] Table 11 Results of fine particle dosage in composition stability samples

[0284]

[0285]

[0286] Comparing the data of sample 11 in the table above with that of sample 5 (0 days) in Table 7, and comparing the data of sample 10 with that of sample 8 (0 days) in Table 8, shows that the dry powder inhalation composition prepared by the method of the present invention can maintain the aerodynamic parameters (APSD) of the dry powder stable and basically unchanged after being stored at an environment not higher than 25°C for 56 days, with a variation range within ±10%.

[0287] Example 7 Accelerated stability study of dry powder inhalation composition

[0288] Samples 5 and 8 were placed under accelerated conditions (40℃±2℃ / RH75%±5%) for one month. The aerodynamic particle size distribution (APSD) of the samples was measured at a flow rate of 60L / min, and the fine particle dose results were calculated using professional software. The specific data are shown in Table 12.

[0289] Table 12 Results of fine particle dose in inhaled compositions after 1 month of accelerated testing

[0290]

[0291] The data in the table above show that the aerodynamic parameters (APSD) of the dry powder inhalation composition prepared by the method of the present invention are stable under accelerated conditions for one month.

[0292] Comparative Example 1: Umeprazole and Vilanterol Triphenylacetic Acid Dry Powder Inhalation Composition

[0293] (i) Formulation and material processing: 98.81% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.60% magnesium stearate; 0.59% micronized umebromide; 0.32% micronized vilanterol triphenylacetate;

[0294] (ii) High shear mixing: The lactose and magnesium stearate from step (i) were placed in a high shear mixer and mixed at 600 rpm for 7.5 minutes to obtain the excipient mixture;

[0295] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the total amount of micronized triphenylacetic acid vilanterol and umembranosine bromide from step (i) in a 4:1 ratio and then passed through a 60-mesh sieve to obtain the raw material and excipient mixture.

[0296] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 30 rpm for 30 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 13.

[0297] Table 13 Content results of Comparative Example 1

[0298]

[0299] Compared with the content results of Examples 4-2 (see Table 4), the content of Comparative Example 1 (Table 13) decreased to about 95%, and the RSD value increased. It can be seen that sieving after mixing the excipient mixture with the micronized active pharmaceutical ingredient at a mass ratio of 4:1 will increase the loss of active pharmaceutical ingredient and increase the content RSD value.

[0300] Comparative Example 2: Umeprazole dry powder inhalation composition

[0301] (i) Formulation and material processing: 98.81% lactose monohydrate, passed through a 40-mesh sieve for later use; 0.60% magnesium stearate; 0.59% micronized umelemonamine bromide;

[0302] (ii) High shear mixing: The lactose and magnesium stearate from step (i) were placed in a high shear mixer and mixed at 600 rpm for 7.5 minutes to obtain the excipient mixture;

[0303] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the micronized umelemonamine bromide from step (i) at a ratio of 30:1 and then passed through a 60-mesh sieve to obtain the excipient mixture.

[0304] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a three-dimensional mixer and mixed at 30 rpm for 30 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 14.

[0305] Table 14 Content results of Comparative Example 2

[0306] Comparative Example Active ingredients content(%) RSD(%, n=10) Comparative Example 2 Umeprazole 97.46 1.75

[0307] Compared with the content results of Comparative Example 2 (Table 14), there was no significant difference in content and RSD value. It can be seen that the content of the dry powder inhalation composition was not significantly affected by the mixing of excipient mixture and micronized active pharmaceutical ingredient at a mass ratio of 30:1 and then sieved. However, the mixing time was extended due to the increased proportion of excipient mixture.

[0308] Comparative Example 3: Vilanterol Triphenylacetic Acid Dry Powder Inhalation Composition

[0309] (i) Formulation and material handling: 98.68% lactose monohydrate, passed through a 40-mesh sieve for later use; 1% magnesium stearate; 0.32% micronized vilanterol triphenylacetic acid;

[0310] (ii) High shear mixing: The lactose and magnesium stearate from step (i) are placed in a high shear mixer and mixed at 500 rpm for 6 minutes to obtain the excipient mixture;

[0311] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the micronized triphenylacetic acid vilanterol from step (i) at a ratio of 7:1 and then passed through a 60-mesh sieve to obtain the excipient mixture.

[0312] (iv) Preparation method of the composition: The remaining excipient mixture from step (ii) and the raw and excipient mixture from step (iii) are placed in a high shear mixer and mixed at 500 rpm for 10 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 15.

[0313] Table 15 Content results for Comparative Example 3

[0314] Comparative Example Active ingredients content(%) RSD(%, n=10) Comparative Example 3 Vilantro 93.67 2.09

[0315] Comparative Example 4: Vilanterol Triphenylacetic Acid Dry Powder Inhalation Composition

[0316] (i) Formulation and material handling: 98.68% lactose monohydrate, passed through a 40-mesh sieve for later use; 1% magnesium stearate; 0.32% micronized vilanterol triphenylacetic acid;

[0317] (ii) Three-dimensional mixing: The lactose and magnesium stearate from step (i) are placed in a three-dimensional mixer and mixed at 30 rpm for 30 minutes to obtain the excipient mixture;

[0318] (iii) Screening of active pharmaceutical ingredient: The excipient mixture from step (ii) is mixed with the micronized triphenylacetic acid vilanterol from step (i) at a ratio of 7:1 and then passed through a 60-mesh sieve to obtain the excipient mixture.

[0319] (iv) Preparation method of the composition: The excipient mixture of step (ii) and the raw and excipient mixture of step (iii) are placed in a three-dimensional mixer and mixed at 30 rpm for 30 minutes to obtain a dry powder inhalation composition. The content and mixing uniformity results are shown in Table 16.

[0320] Table 16 Content results for Comparative Example 4

[0321] Comparative Example Active ingredients content(%) RSD(%, n=10) Comparative Example 4 Vilantro 97.71 4.12

[0322] As can be seen from the results in Table 16, the RSD value of the excipients and the dry powder inhalation composition prepared by using a three-dimensional mixer was significantly greater than that of Examples 2-1 to 2-3 (see Table 2). This indicates that replacing the first three-dimensional mixing with high-shear mixing for the excipient mixing step, based on two three-dimensional mixing steps, helps to improve the mixing uniformity.

[0323] The dry powder inhalation composition prepared in Comparative Example 4 was filled and coiled together with the aluminum foil blister strips filled in Examples 3-2 and inserted into a specific inhalation device to obtain dry powder inhalation composition sample 12. The aerodynamic particle size distribution (APSD) of the sample was measured at a flow rate of 60 L / min, and the fine particle dose results were calculated using professional software. The specific data are shown in Table 17.

[0324] Table 17. Dosage results of fine particles in sample 12 of the dry powder inhalation composition.

[0325]

[0326] As can be seen from the data in Table 17, in Comparative Example 4, which used a three-dimensional mixer to mix excipients and prepare a dry powder inhalation composition of vilanterol triphenylacetic acid, the fine particle dose (FPD) and fine particle dose percentage (FPF) of the active ingredient in Sample 12 were lower than those in Sample 5 (see Table 7), indicating that the high-shear mixing excipient step helps to increase the amount of deposited in the lungs.

Claims

1. A method for preparing a composition, wherein the pharmaceutical composition comprises an active ingredient and excipients, characterized in that, The preparation method includes step 1: mixing the excipients with the active ingredient to prepare a mixture of raw and excipient materials; The active ingredient is selected from at least one of the following: anticholinergic drugs, β2-receptor agonists, and glucocorticoids.

2. The preparation method according to claim 1, further comprising step 2: The raw material mixture from step 1 is mixed with the excipients in a three-dimensional manner to obtain the composition.

3. The preparation method according to any one of claims 1-2, wherein in step 1 the excipients and the active ingredient are mixed in a ratio of ≥5:

1.

4. The preparation method according to any one of claims 1-3, wherein it satisfies one or more of the following conditions: 1) The excipients include at least one of lactose, magnesium stearate, calcium stearate or talc, preferably, the lactose is selected from at least one of lactose monohydrate or anhydrous lactose; 2) The mixing speed in step 1 is 200-900 rpm, preferably 300-800 rpm, more preferably 350-700 rpm, most preferably 600-700 rpm, or 300-450 rpm, or 300-400 rpm, for example 700 rpm or 650 rpm or 600 rpm or 450 rpm or 400 rpm or 350 rpm; 3) The mixing time in step 1 is 3 to 20 minutes, preferably 4 to 15 minutes, more preferably 5 to 10 minutes, and most preferably 7 to 10 minutes or 4 to 6 minutes, for example 10 minutes or 8.5 minutes or 7.5 minutes or 6 minutes or 5 minutes.

5. The preparation method according to any one of claims 1-4, wherein it satisfies one or more of the following conditions: 1) Step 1 further includes sieving after mixing in step 1. Further, the mesh size of the sieve is ≥24 mesh, preferably 24 mesh to 60 mesh, for example 24 mesh, 30 mesh, 40 mesh or 60 mesh. 2) In step 1, the excipients and active ingredients are mixed in a ratio of ≥5:1 and then sieved, preferably ≥7:1, more preferably 7:1 to 30:1, for example 7:1 or 10:1 or 13:1 or 16:1 or 19:1 or 22:1 or 25:1 or 27:1 or 30:

1.

6. The preparation method according to any one of claims 1-5, wherein it satisfies one or more of the following conditions: 1) The rotational speed of the three-dimensional mixing in step 2 is ≥10 rpm, preferably ≥15 rpm, more preferably 15-60 rpm, and most preferably 15-45 rpm or 20-40 rpm, for example 20 rpm or 25 rpm or 30 rpm or 35 rpm or 40 rpm. 2) The mixing time for three-dimensional mixing in step 2 is ≥10 min, preferably 10-60 min, more preferably 10-50 min, and most preferably 15-45 min, for example 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, or 45 min.

7. The preparation method according to any one of claims 1-6, wherein, The active ingredient is selected from at least one of the following: anticholinergic drugs, β2-receptor agonists, and glucocorticoids.

8. The preparation method according to any one of claims 1-7, wherein, The anticholinergic drugs include, but are not limited to, one or more of tiotropium bromide, glycopyrronium bromide, umeclidinium bromide, adecyl bromide, ipratropium bromide, oxybutynin chloride, and troxetine chloride; The β2-receptor agonists include, but are not limited to, one or more of indacaterol or its salts, formoterol or its salts, vilanterol or its salts, salmeterol or its salts, and olodaterol or its salts, preferably selected from vilanterol or its salts, or salmeterol or its salts; The glucocorticoids include, but are not limited to, budesonide, mometasone or its esters, fluticasone or its esters, beclomethasone or its esters, and preferably selected from, or selected from, mometasone furoate, fluticasone furoate, fluticasone propionate, and beclomethasone dipropionate.

9. The preparation method according to claims 1-8, wherein the active ingredient and the excipients have one or more of the following characteristics: 1) The weight percentage of the active ingredient is 0.01% to 10%; 2) The particle size distribution of the active ingredient is D 50 ≤4.5μm; 3) The mass percentage of the excipients is ≥90%; 4) The particle size distribution of the excipient is D 90 ≤200μm.

10. The preparation method according to any one of claims 1-9, wherein the active ingredients in the composition may be provided as individually packaged components or as a mixture thereof.

11. A composition prepared by any one of the preparation methods according to claims 1-10; preferably, the composition is a dry powder composition, more preferably, the composition is a dry powder inhalation composition.

12. A delivery device comprising the composition of claim 11.

13. Use of the composition of claim 11 or the delivery device of claim 12 in the preparation of a medicament for treating or preventing inflammatory diseases or respiratory diseases.

Images