Dry powder inhalation composition as well as preparation method and drug delivery system thereof

Abstract

The invention relates to a dry powder inhalation composition as well as a preparation method and a drug delivery system thereof. The dry powder inhalation composition comprises a base material and an active component, and the preparation method comprises the following steps: carrying out first high shear mixing on the base material to prepare an intermediate material; carrying out second high shear mixing on the intermediate material and the active component; wherein the rotating speed of the first high-shear mixing is greater than or equal to 150rpm; the rotating speed of the second-time high-shear mixing is greater than or equal to 150rpm. The preparation method of the dry powder inhalation composition is simple in step and short in time consumption, and meanwhile, the high lung deposition rate of the medicine can be kept.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical technology, and particularly to a dry powder inhalation composition, a preparation method thereof, and a drug delivery system. Background Art

[0002] Respiratory diseases are one of the diseases with relatively heavy burdens. Among them, pneumonia and chronic lower respiratory diseases account for a relatively large proportion. Among chronic lower respiratory diseases, asthma and chronic obstructive pulmonary disease (COPD) are more common. Asthma usually recurs frequently, affecting lung function, and severe acute attacks can even endanger life. The treatment of asthma mainly relies on inhaled preparations. Inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) are the first choices for long-term maintenance treatment of moderate to severe asthma patients over 6 years old. COPD cannot be cured and requires long-term medication. Inhalation is the main administration route, mainly using bronchodilators such as anticholinergic drugs and LABA. Frequent medical visits and hospitalizations have an important impact on the quality of life, daily activities, and general health status of patients with chronic lower respiratory diseases, and pose a huge burden on the health system. However, for both asthma and COPD, there is still a large room for improvement in the drug treatment effect.

[0003] Dry powder inhalers (DPI), also known as inhaled powder aerosols, are a new dosage form developed on the basis of metered-dose inhalers by integrating powder technology knowledge. It is a drug delivery system in which micronized drugs are either alone or mixed with a carrier, and then through a special drug delivery device, by the patient's active inhalation, the drug is dispersed into a mist and enters the respiratory tract to exert local or systemic effects. Compared with other dosage forms of inhaled preparations (such as aerosols and inhaled liquid preparations), dry powder inhalers have the advantages of being environmentally friendly (without fluorinated gas propellants), good product stability, convenient use and good coordination, accurate delivery dose, and high lung deposition rate. Because of the above advantages, although the drug delivery device of dry powder inhalers is relatively complex and the R & D technology is more difficult, with the application of particle engineering technology and nanotechnology and the optimization of inhaler devices, globally, the market of dry powder inhalers is continuously expanding, and its R & D has become the mainstream.

[0004] In dry powder inhalers, the carrier is mainly used to adsorb drug particles, enhance the stability of the drug during storage, increase the fluidity of the drug at the same time, facilitate the drug to smoothly enter the lower respiratory tract, and reduce the adsorption in the oral cavity and throat. When the patient inhales, the shear force generated by air turbulence separates the drug from the carrier. Small particles enter the lower respiratory tract, while large particle carriers or drugs fall into the oral cavity and throat. The greater the shear force generated by air turbulence, the higher the proportion of drug particles successfully separated from the carrier and the higher the lung deposition rate.

[0005] The pulmonary deposition rate of dry powder inhalers is closely related to the formulation process, especially the mixing process, which directly affects the dispersion effect of the drug and ultimately affects the pulmonary deposition rate of the product. At present, in order to ensure the pulmonary deposition rate of the drug, a mixing process with cumbersome steps and the need to mix materials in multiple batches (not less than 3 times) or for a long time (not less than 3h) is usually adopted, resulting in low production efficiency. Summary of the Invention

[0006] Based on this, the present application provides a dry powder inhalation composition, a preparation method thereof, and a drug delivery system. The preparation method of the dry powder inhalation composition has simple steps and short time consumption, and can also maintain a high pulmonary deposition rate of the drug.

[0007] In the first aspect of the present application, a preparation method of a dry powder inhalation composition is provided. The dry powder inhalation composition includes a substrate and an active ingredient. The preparation method includes the following steps:

[0008] Perform the first high-shear mixing on the substrate to prepare an intermediate material;

[0009] Perform the second high-shear mixing on the intermediate material and the active ingredient;

[0010] Wherein, the rotation speed of the first high-shear mixing ≥ 150 rpm;

[0011] The rotation speed of the second high-shear mixing ≥ 150 rpm.

[0012] In one embodiment, the rotation speed of the first high-shear mixing is 150 rpm - 850 rpm, and the time is 5 min - 60 min.

[0013] In one embodiment, the rotation speed of the first high-shear mixing is 200 rpm - 800 rpm.

[0014] In one embodiment, the rotation speed of the second high-shear mixing is 150 rpm - 850 rpm, and the time is 5 min - 60 min.

[0015] In one embodiment, the rotation speed of the second high-shear mixing is 200 rpm - 800 rpm.

[0016] In one embodiment, the substrate includes lactose;

[0017] Optionally, the lactose is in the form of a hydrate. Further optionally, the lactose is lactose monohydrate;

[0018] Optionally, the substrate further includes magnesium stearate.

[0019] In one embodiment, in the dry powder inhalation composition, the mass percentage of lactose monohydrate is ≥90%, and the mass percentage of magnesium stearate is 0 to 0.2%.

[0020] In one embodiment, the active ingredient has at least one of the following characteristics:

[0021] (1) The active ingredient includes one or more of an anticholinergic drug, a long-acting β2-agonist (LABA), and an inhaled corticosteroid (ICS);

[0022] (2) The particle size distribution of the active ingredient is D 50 ≤5 μm, and D 90 ≤10 μm.

[0023] In a second aspect of the present application, there is provided a dry powder inhalation composition prepared by the preparation method described in the first aspect.

[0024] In a third aspect of the present application, there is provided a drug delivery system, including a dry powder inhalation device and the dry powder inhalation composition described in the second aspect accommodated in the dry powder inhalation device.

[0025] The above dry powder inhalation composition is mixed by a high-shear mixing method and with a suitable rotation speed, which can complete the mixing in a shorter time and only requires two mixings. Compared with the traditional method, the mixing time is significantly reduced, the production process is reduced, and the prepared dry powder inhalation composition has a high pulmonary deposition rate, which can effectively balance the production efficiency and drug efficacy of the dry powder inhaler. It has the advantages of simple preparation process, easy commercial production, and increased pulmonary deposition of the active ingredient, and realizes that the quality index of the above dry powder inhalation composition is not inferior to that of commercially available products. It is suitable for treating respiratory diseases such as asthma and chronic obstructive pulmonary disease, and has broad application prospects. Detailed Embodiments

[0026] The following further describes the dry powder inhalation composition of the present application, its preparation method, and the drug delivery system in detail with reference to specific embodiments. The present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the understanding of the disclosed content of the present application more thorough and comprehensive.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this application belongs. The terms used in the specification of this application herein are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0028] As used herein, "one or more" means any one, any two, or any two or more of the listed items.

[0029] In this application, terms such as "first aspect", "second aspect", and "third aspect" are for descriptive purposes only, and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly specifying the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", etc. are only for non-exhaustive enumerative description purposes, and should be understood not to constitute a closed limitation on quantity.

[0030] In this application, among the technical features described in an open-ended manner, there are closed technical solutions composed of the listed features, as well as open technical solutions including the listed features.

[0031] In this application, regarding numerical ranges, unless otherwise specified, the above numerical ranges are considered continuous, and include the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when the range refers to integers, it includes each integer between the minimum and maximum values of the range. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0032] In this application, for the percentage content involved, unless otherwise specified, for solid-liquid mixing and solid-solid mixing, it refers to mass percentage, and for liquid-liquid mixing, it refers to volume percentage.

[0033] In this application, for the percentage concentration involved, unless otherwise specified, it refers to the final concentration. The final concentration refers to the proportion of the added component in the system after adding the component.

[0034] In this application, for the temperature parameter, unless otherwise specified, it allows both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument.

[0035] The terms "high-shear mixer" and "high-energy mixer" have the same meaning. "High-shear mixing" is a way to achieve material mixing through the rotation of the impeller at different mixing times and mixing speeds. Without limitation, typical high-energy mixers are P100 and P300 (Diosna GmbH, Germany), Roto Mix (IMA, Italy), CyclomixTM (Hosokawa Micron Group Ltd, Japan), and TRV (GEA, Germany).

[0036] The term "rpm" refers to the unit of rotational speed. rpm is the abbreviation of revolutions per minute, indicating the rotational speed per minute. For example, 200 rpm means 200 revolutions per minute.

[0037] The term "lung deposition rate" refers to the percentage of the active ingredient particles of an inhaled preparation that can reach the deep lungs of a patient.

[0038] The term "D 50 " refers to the particle size corresponding to when the cumulative particle size distribution percentage reaches 50%. Its physical meaning is that 50% of the particles are larger than it and 50% of the particles are smaller than it.

[0039] The term "D 90 " refers to the particle size corresponding to when the cumulative particle size distribution percentage reaches 90%. Its physical meaning is that 10% of the particles are larger than it and 90% of the particles are smaller than it.

[0040] Some examples of the present application provide a method for preparing a dry powder inhalation composition, the dry powder inhalation composition comprising a substrate and an active ingredient, the preparation method comprising the following steps:

[0041] Perform a first high-shear mixing on the substrate to prepare an intermediate material;

[0042] Perform a second high-shear mixing on the intermediate material and the active ingredient;

[0043] Wherein, the rotation speed of the first high-shear mixing ≥ 150 rpm;

[0044] The rotation speed of the second high-shear mixing ≥ 150 rpm.

[0045] In some of these examples, the total time consumed for the second high-shear mixing and the second high-shear mixing ≤ 120 min. Specifically, the total time consumed includes but is not limited to: 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, 65 min, 70 min, 80 min, 90 min, 100 min, 110 min, 120 min or the range between any two of the foregoing.

[0046] In some of these examples, the rotation speed of the first high-shear mixing is 150 rpm to 850 rpm. Specifically, the rotation speed of the first high-shear mixing includes but is not limited to: 150 rpm, 200 rpm, 250 rpm, 300 rpm, 350 rpm, 400 rpm, 450 rpm, 500 rpm, 550 rpm, 600 rpm, 650 rpm, 700 rpm, 750 rpm, 800 rpm, 850 rpm or the range between any two of the foregoing. Further, the rotation speed of the first high-shear mixing is 200 rpm to 800 rpm. Still further, the rotation speed of the first high-shear mixing is 200 rpm to 500 rpm.

[0047] In some of these examples, the time of the first high-shear mixing is 5 min to 60 min. Specifically, the time of the first high-shear mixing includes, but is not limited to: 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, or the range between any two of the foregoing. Further, the time of the first high-shear mixing is 5 min to 30 min.

[0048] In some of these examples, the rotation speed of the first high-shear mixing is 200 rpm to 500 rpm, and the time is 5 min to 30 min.

[0049] In some of these examples, the rotation speed of the second high-shear mixing is 150 rpm to 850 rpm. Specifically, the rotation speed of the second high-shear includes, but is not limited to: 150 rpm, 200 rpm, 250 rpm, 300 rpm, 350 rpm, 400 rpm, 450 rpm, 500 rpm, 550 rpm, 600 rpm, 650 rpm, 700 rpm, 750 rpm, 800 rpm, 850 rpm, or the range between any two of the foregoing. Further, the rotation speed of the second high-shear mixing is 200 rpm to 800 rpm. Still further, the rotation speed of the second high-shear mixing is 200 rpm to 600 rpm.

[0050] In some of these examples, the time of the second high-shear mixing is 5 min to 60 min. Specifically, the time of the second high-shear mixing includes, but is not limited to: 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, or the range between any two of the foregoing. Further, the time of the second high-shear mixing is 5 min to 30 min.

[0051] In some of these examples, the rotation speed of the second high-shear mixing is 200 rpm to 600 rpm, and the time is 5 min to 30 min.

[0052] It can be understood that the substrate is a substrate for dry powder inhalation.

[0053] In some of these examples, the substrate includes lactose. Further, the lactose is in the form of a hydrate. Without limitation, the lactose is lactose monohydrate.

[0054] Without limitation, lactose is used as a carrier material in the dry powder inhalation composition, and its particle size distribution can be D10 is from 3 μm to 10 μm, D 50 is from 30 μm to 70 μm, D 90 is from 100 μm to 200 μm.

[0055] In some of these examples, the substrate further comprises magnesium stearate. Magnesium stearate acts as a lubricant in the dry powder inhalation composition.

[0056] In some of these examples, in the dry powder inhalation composition, the mass percentage of lactose monohydrate is ≥ 90%, and the mass percentage of magnesium stearate is 0 to 0.2%. Specifically, in the dry powder inhalation composition, the mass percentage of lactose monohydrate includes but is not limited to: 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or the range between any two of the foregoing. Specifically, in the dry powder inhalation composition, the mass percentage of magnesium stearate includes but is not limited to: 0%, 0.01%, 0.03%, 0.05%, 0.07%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.2% or the range between any two of the foregoing.

[0057] In some of these examples, the active ingredient includes one or more of an anticholinergic, a long-acting β2-agonist (LABA), and an inhaled corticosteroid (ICS).

[0058] Without limitation, the anticholinergic is selected from glycopyrronium bromide, tiotropium bromide, aclidinium bromide, umeclidinium bromide, revefenacin, and one or more of pharmaceutically acceptable salts or hydrates of these compounds.

[0059] Without limitation, the long-acting β2-agonist is selected from indacaterol, formoterol, salmeterol, olodaterol, vilanterol, and one or more of pharmaceutically acceptable salts or hydrates of these compounds.

[0060] Without limitation, the inhaled corticosteroid is selected from beclomethasone dipropionate, budesonide, fluticasone propionate, fluticasone furoate, mometasone furoate, and one or more of pharmaceutically acceptable salts or hydrates of these compounds.

[0061] It can be understood that the active ingredient is in the form of micronized particles. In some of these examples, the particle size distribution of the active ingredient is D 50 ≤ 5 μm, and D 90 ≤ 10 μm. The physiological structure of the lungs requires that the drug particles of the dry powder inhaler be very fine. Reasonably controlling the particle size of the active ingredient is conducive to the particles entering the bronchioles and not being easily exhaled with breathing, thereby improving the pulmonary deposition rate.

[0062] Without limitation, some types of active ingredients (such as glycopyrronium bromide) can be co - micronized by first mixing with a small amount of magnesium stearate.

[0063] In some of these examples, the dry powder inhalation composition comprises a substrate and an active ingredient, the substrate being lactose and magnesium stearate, and the method for preparing the dry powder inhalation composition comprises the following steps:

[0064] Co - micronize a portion of the magnesium stearate with some types of active ingredients, and then use them together with the remaining separately micronized active ingredients as the active ingredient;

[0065] Mix the remaining magnesium stearate with lactose as the substrate for the first high - shear mixing to prepare an intermediate material;

[0066] Perform a second high - shear mixing of the intermediate material with the active ingredient.

[0067] Without limitation, by mass percentage, the ratio of some types of active ingredients to a portion of the magnesium stearate is 80%:20% to 99%:1%. Specifically, the ratio of some types of active ingredients to a portion of the magnesium stearate includes but is not limited to: 80%:20%, 83%:17%, 85%:15%, 88%:12%, 90%:10%, 92%:8%, 95%:5%, 97%:3%, 99%:1% or the range between any two of the foregoing.

[0068] Additionally without limitation, after completing the second high - shear mixing, in order to improve the uniformity of the active ingredient distribution, a further mixing step can be added.

[0069] Some other examples of the present application also provide a dry powder inhalation composition prepared by the preparation method as described above.

[0070] Some other examples of the present application also provide a drug delivery system, comprising a dry powder inhalation device and the dry powder inhalation composition as described above accommodated in the dry powder inhalation device. The dry powder inhalation composition of the present application can be used in combination with a dry powder inhalation device to treat respiratory diseases such as asthma and chronic obstructive pulmonary disease.

[0071] For the experimental parameters not specified in the following specific examples, preference is given to the guidance provided in the present application document, and it is also possible to refer to experimental manuals in the art or other experimental methods known in the art, or to the experimental conditions recommended by the manufacturer.

[0072] The raw materials and reagents involved in the following specific examples can be obtained commercially, or those skilled in the art can prepare them according to known means.

[0073] The high-energy mixer is a device purchased from GEA Company in Germany, and the new generation impactor (NGI) is a device purchased from COPLEY Company in the UK.

[0074] The commercial product is indacaterol / glycopyrronium / mometasone furoate inhalation powder (I) from Novartis, with a specification of 150 μg / 50 μg / 80 μg (calculated as indacaterol acetate, glycopyrronium bromide, and mometasone furoate respectively).

[0075] Example 1

[0076] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following base materials and active ingredients are provided:

[0077] (i) Base materials: 98.59% of lactose monohydrate, 0.15% of magnesium stearate;

[0078] (ii) Active ingredients: micronized particles of 0.25% of glycopyrronium bromide, 0.69% of indacaterol acetate, and 0.32% of mometasone furoate. Among them, indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the base material at a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5 μm, and D 90 ≤10 μm;

[0079] Then, the following preparation method of the composition is provided:

[0080] (i) Place lactose monohydrate and the remaining magnesium stearate in a high-energy mixer and mix at a speed of 300 rpm for 10 minutes to obtain an adjuvant mixture;

[0081] (ii) Place the adjuvant mixture obtained in step (i) and the active ingredients in a high-energy mixer and mix at a speed of 500 rpm for 15 minutes to obtain the dry powder inhalation composition.

[0082] Load the above dry powder inhalation composition into No. 3 HPMC (hydroxypropyl methylcellulose) capsules, with a filling amount of 25 mg.

[0083] Use the new generation impactor (NGI) to measure the aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data are shown in Table 1:

[0084] Table 1 APSD indicators of the sample in Example 1 and the commercial product

[0085]

[0086] Note: The delivered dose is the dose released from the device when the inhalation preparation is used; FPD is the fine particle dose; FPF is the percentage of fine particles.

[0087] It can be seen that all the APSD indicators of the sample of Example 1 are not worse than those of the commercial product (the numerical difference is within ±15%), and the total mixing time of Example 1 is only 25 minutes, only 2 times of mixing are required, the mixing time is short, the production efficiency is high, and the production steps are simple.

[0088] Example 2

[0089] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following base materials and active ingredients are provided:

[0090] (i) Base materials: 98.59% of lactose monohydrate, 0.15% of magnesium stearate;

[0091] (ii) Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate, and 0.32% mometasone furoate. Among them, indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the base material according to a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5μm, and D 90 ≤10μm;

[0092] Then, the following preparation method of the composition is provided:

[0093] (i) Place lactose monohydrate and the remaining magnesium stearate in a high-energy mixer and mix at a speed of 300 rpm for 10 minutes to obtain an excipient mixture;

[0094] (ii) Place the excipient mixture obtained in step (i) and the active ingredients in a high-energy mixer and mix at a speed of 500 rpm for 10 minutes to obtain the dry powder inhalation composition.

[0095] Load the above dry powder inhalation composition into a No. 3 HPMC capsule, with a filling amount of 25 mg.

[0096] Use a new generation impactor (NGI) to measure the aerodynamic particle size distribution (APSD) of the above capsule sample and the commercial product at a flow rate of 60 L / min. The specific data are shown in Table 2:

[0097] Table 2 APSD indicators of the sample of Example 2 and the commercial product

[0098]

[0099] All the APSD indicators of the sample of Example 2 are not inferior to those of the commercial product (the numerical difference is within ±15%), and the total mixing time of Example 2 is only 20 minutes, with only 2 times of mixing. The mixing time is short, the production efficiency is high, and the production steps are simple.

[0100] Example 3

[0101] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following base materials and active ingredients are provided:

[0102] (i) Base materials: 98.59% of lactose monohydrate, 0.15% of magnesium stearate;

[0103] (ii) Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate, and 0.32% mometasone furoate. Among them, indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the base material according to a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5μm, and D 90 ≤10μm;

[0104] Next, the following preparation method of the composition is provided:

[0105] (i) Place lactose monohydrate and the remaining magnesium stearate in a high-energy mixer and mix at a speed of 200 rpm for 60 minutes to obtain an excipient mixture;

[0106] (ii) Place the excipient mixture obtained in step (i) and the active ingredients in a high-energy mixer and mix at a speed of 200 rpm for 60 minutes to obtain the dry powder inhalation composition.

[0107] Load the above dry powder inhalation composition into No. 3 HPMC capsules, with a filling amount of 25 mg.

[0108] Using a new generation impactor (NGI), measure the aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data are shown in Table 3:

[0109] Table 3 APSD indicators of the sample of Example 3 and commercial products

[0110]

[0111] All the APSD indicators of the sample of Example 3 are not inferior to those of the commercial product (the numerical difference is within ±15%). Compared with Example 1, if the mixing speed is reduced to 200 rpm, the mixing time needs to be extended accordingly.

[0112] Example 4

[0113] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following base materials and active ingredients are provided:

[0114] (i) Base materials: 98.59% of lactose monohydrate, 0.15% of magnesium stearate;

[0115] (ii) Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate, and 0.32% mometasone furoate. Among them, indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of the magnesium stearate in the base material at a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5 μm, and D 90 ≤10 μm;

[0116] Next, a preparation method for the following composition is provided:

[0117] (i) Place lactose monohydrate and the remaining magnesium stearate in a high-energy mixer and mix at a speed of 800 rpm for 5 minutes to obtain an excipient mixture;

[0118] (ii) Place the excipient mixture obtained in step (i) and the active ingredients in a high-energy mixer and mix at a speed of 800 rpm for 5 minutes to obtain the dry powder inhalation composition.

[0119] Load the above dry powder inhalation composition into a No. 3 HPMC capsule, with a filling amount of 25 mg.

[0120] Use a Next Generation Impactor (NGI) to measure the aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data is shown in Table 4:

[0121] Table 4 APSD indicators of the sample of Example 4 and commercial products

[0122]

[0123] All the APSD indicators of the sample of Example 4 are not worse than those of the commercial product (the numerical difference is within ±15%). Compared with Example 1, if the mixing speed is increased to 800 rpm, the mixing time can be correspondingly shortened.

[0124] Example 5

[0125] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following base materials and active ingredients are provided:

[0126] (i) Base materials: 98.59% of lactose monohydrate, 0.15% of magnesium stearate;

[0127] (ii)Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate, and 0.32% mometasone furoate, wherein indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the base material at a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5 μm, and D 90 ≤10 μm;

[0128] The preparation method of the following composition is further provided:

[0129] (i)Place lactose monohydrate and the remaining magnesium stearate in a high-energy mixer and mix at a speed of 150 rpm for 60 minutes to obtain an excipient mixture;

[0130] (ii)Place the excipient mixture obtained in step (i) and the active ingredients in a high-energy mixer and mix at a speed of 150 rpm for 60 minutes to obtain the dry powder inhalation composition.

[0131] Load the above dry powder inhalation composition into No. 3 HPMC capsules, with a filling amount of 25 mg.

[0132] Use a Next Generation Impactor (NGI) to measure the Aerodynamic Particle Size Distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data are shown in Table 5:

[0133] Table 5 APSD indicators of the sample of Example 5 and commercial products

[0134]

[0135] Compared with Example 3, if the mixing speed is reduced to 150 rpm, each index of the APSD of the sample is slightly lower than that of the commercial product (the value is more than 15% lower), indicating that the mixing speed is preferably not less than 200 rpm.

[0136] Example 6

[0137] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following base material and active ingredients are provided:

[0138] (i)Base material: 98.59% lactose monohydrate, 0.15% magnesium stearate;

[0139] (ii)Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate and 0.32% mometasone furoate, wherein indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the substrate in a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5 μm, and D 90 ≤10 μm;

[0140] The preparation method of the following composition is further provided:

[0141] (i)Put lactose monohydrate and the remaining magnesium stearate into a high-energy mixer and mix at a speed of 850 rpm for 5 minutes to obtain an excipient mixture;

[0142] (ii)Put the excipient mixture obtained in step (i) and the active ingredients into a high-energy mixer and mix at a speed of 850 rpm for 5 minutes to obtain the dry powder inhalation composition.

[0143] Put the above dry powder inhalation composition into No. 3 HPMC capsules, with a filling amount of 25 mg.

[0144] Use a Next Generation Impactor (NGI) to measure the Aerodynamic Particle Size Distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data is shown in Table 6:

[0145] Table 6 APSD indicators of the sample of Example 6 and commercial products

[0146]

[0147] Compared with Example 4, if the mixing speed is increased to 850 rpm, each APSD index of the sample is not worse than that of the commercial product (the numerical difference is within ±15%), but the APSD index is lower than that of Example 4, and the numerical difference from the reference is close to 15%. It shows that the mixing speed is preferably not higher than 800 rpm.

[0148] Example 7

[0149] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following substrates and active ingredients are provided:

[0150] (i)Substrate: 98.59% lactose monohydrate, 0.15% magnesium stearate;

[0151] (ii)Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate and 0.32% mometasone furoate, wherein indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the base material in a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5 μm, and D 90 ≤10 μm;

[0152] The preparation method is as follows:

[0153] (i)Place lactose monohydrate and the remaining magnesium stearate in a high-energy mixer and mix at a speed of 800 rpm for 5 minutes to obtain an excipient mixture;

[0154] (ii)Place the excipient mixture obtained in step (i) and the active ingredients in a high-energy mixer and mix at a speed of 200 rpm for 60 minutes to obtain the dry powder inhalation composition.

[0155] Load the above dry powder inhalation composition into No. 3 HPMC capsules, with a filling amount of 25 mg.

[0156] Use a Next Generation Impactor (NGI) to measure the aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data are shown in Table 7:

[0157] Table 7 APSD indicators of the sample of Example 7 and commercial products

[0158]

[0159] Compared with Example 3, after increasing the rotation speed of mixing (i) from 200 rpm to 800 rpm, the APSD indicators of the sample are still not worse than those of the commercial product (the numerical difference is within ±15%), which verifies again that the preferred range of the mixing rotation speed is 200 rpm to 800 rpm.

[0160] Example 8

[0161] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following base materials and active ingredients are provided:

[0162] (i)Base material: 98.59% lactose monohydrate, 0.15% magnesium stearate;

[0163] (ii)Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate, and 0.32% mometasone furoate, wherein indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the substrate in a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5 μm, and D 90 ≤10 μm;

[0164] A preparation method of the following composition is further provided:

[0165] (i)Place lactose monohydrate and the remaining magnesium stearate in a high-energy mixer and mix at a speed of 200 rpm for 60 minutes to obtain an excipient mixture;

[0166] (ii)Place the excipient mixture obtained in step (i) and the active ingredients in a high-energy mixer and mix at a speed of 800 rpm for 5 minutes to obtain the dry powder inhalation composition.

[0167] Fill the above dry powder inhalation composition into No. 3 HPMC capsules, with a filling amount of 25 mg.

[0168] Use a next-generation impactor (NGI) to measure the aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data are shown in Table 8:

[0169] Table 8 APSD indexes of the sample of Example 8 and commercial products

[0170]

[0171] Compared with Example 3, after increasing the rotation speed of mixing (ii) from 200 rpm to 800 rpm, the APSD indexes of the sample are still not worse than those of the commercial product (the numerical difference is within ±15%), which verifies again that the preferred range of the mixing rotation speed is 200 rpm to 800 rpm.

[0172] Example 9

[0173] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following substrates and active ingredients are provided:

[0174] (i)Substrate: 98.59% lactose monohydrate, 0.15% magnesium stearate;

[0175] (ii)Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate and 0.32% mometasone furoate, wherein indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the base material in a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5 μm, and D 90 ≤10 μm;

[0176] The preparation method is as follows:

[0177] (i)Place lactose monohydrate and the remaining magnesium stearate in a high-energy mixer and mix at a speed of 850 rpm for 5 minutes to obtain an excipient mixture;

[0178] (ii)Place the excipient mixture obtained in step (i) and the active ingredients in a high-energy mixer and mix at a speed of 200 rpm for 60 minutes to obtain the dry powder inhalation composition.

[0179] Load the above dry powder inhalation composition into No. 3 HPMC capsules, with a filling amount of 25 mg.

[0180] Use a Next Generation Impactor (NGI) to measure the Aerodynamic Particle Size Distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data are shown in Table 9:

[0181] Table 9 APSD indicators of the sample of Example 9 and commercial products

[0182]

[0183] Compared with Example 7, after increasing the rotation speed of mixing (i) from 800 rpm to 850 rpm, although the APSD indicators of the sample are not worse than those of the commercial product (the numerical difference is within ±15%), the APSD indicators are lower than those of Example 7, and the numerical difference from the reference is close to 15%, which verifies again that the preferred mixing rotation speed is not higher than 800 rpm.

[0184] Example 10

[0185] This example provides a dry powder inhalation composition. First, in terms of mass percentage, provide the following base material and active ingredients:

[0186] (i)Base material: 98.59% lactose monohydrate, 0.15% magnesium stearate;

[0187] (ii)Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate and 0.32% mometasone furoate, wherein indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the base material at a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5 μm, and D 90 ≤10 μm;

[0188] The preparation method of the following composition is further provided:

[0189] (i)Put lactose monohydrate and the remaining magnesium stearate into a high-energy mixer and mix at a speed of 150 rpm for 60 minutes to obtain an excipient mixture;

[0190] (ii)Put the excipient mixture obtained in step (i) and the active ingredients into a high-energy mixer and mix at a speed of 200 rpm for 60 minutes to obtain the dry powder inhalation composition.

[0191] Fill the above dry powder inhalation composition into No. 3 HPMC capsules, with a filling amount of 25 mg.

[0192] Use a new generation impactor (NGI) to measure the aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data is shown in Table 10:

[0193] Table 10 APSD indexes of the sample of Example 10 and commercial products

[0194]

[0195] Compared with Example 3, after reducing the rotation speed of mixing (i) from 200 rpm to 150 rpm, each index of the APSD of the sample is slightly lower than that of the commercial product (the value is more than 15% lower), which verifies again that the preferred mixing rotation speed is not less than 200 rpm.

[0196] Example 11

[0197] This example provides a dry powder inhalation composition. First, in terms of mass percentage, the following base material and active ingredients are provided:

[0198] (i)Base material: 98.59% lactose monohydrate, 0.15% magnesium stearate;

[0199] (ii)Active ingredients: micronized particles of 0.25% glycopyrronium bromide, 0.69% indacaterol acetate and 0.32% mometasone furoate, wherein indacaterol acetate is micronized alone, mometasone furoate is micronized alone, and glycopyrronium bromide is co-micronized with a part of magnesium stearate in the substrate at a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5 μm, and D 90 ≤10 μm;

[0200] The preparation method is as follows:

[0201] (i)Put lactose monohydrate and the remaining magnesium stearate into a high-energy mixer and mix at a speed of 200 rpm for 60 minutes to obtain an excipient mixture;

[0202] (ii)Put the excipient mixture obtained in step (i) and the active ingredients into a high-energy mixer and mix at a speed of 850 rpm for 5 minutes to obtain the dry powder inhalation composition.

[0203] Fill the above dry powder inhalation composition into No. 3 HPMC capsules, with a filling amount of 25 mg.

[0204] Use a Next Generation Impactor (NGI) to measure the Aerodynamic Particle Size Distribution (APSD) of the above capsule samples and commercial products at a flow rate of 60 L / min. The specific data is shown in Table 11:

[0205] Table 11 APSD indicators of the sample of Example 11 and commercial products

[0206]

[0207] Compared with Example 8, after increasing the rotation speed of mixing (ii) from 800 rpm to 850 rpm, although each APSD index of the sample is not worse than that of the commercial product (the numerical difference is within ±15%), the APSD index is lower than that of Example 8, and the numerical difference from the reference is close to 15%, which verifies again that the preferred mixing rotation speed is not more than 800 rpm.

[0208] Example 12

[0209] This example provides a dry powder inhalation composition. First, in terms of mass percentage, provide the following substrate and active ingredients:

[0210] (i)Substrate: 98.59% lactose monohydrate, 0.15% magnesium stearate;

[0211] (ii) Active ingredient: micronized particles of 0.25% glycopyrrolate, 0.69% indacaterol acetate, and 0.32% mometasone furoate, wherein indacaterol acetate is micronized separately, mometasone furoate is micronized separately, and glycopyrrolate and a portion of magnesium stearate in the base material are co-micronized at a ratio of 90:10 (w / w). The particle size distribution of the micronized particles of the three active ingredients is D 50 ≤5μm, and D 90 ≤10μm;

[0212] The present invention further provides a method for preparing the following composition:

[0213] (i) mixing lactose monohydrate and the remaining magnesium stearate in a high-energy mixer at 200 rpm for 60 minutes to obtain an excipient mixture;

[0214] (ii) The excipient mixture obtained in step (i) and the active ingredient are placed in a high-energy mixer and mixed at a rotation speed of 150 rpm for 60 minutes to obtain the dry powder inhalation composition.

[0215] The above dry powder inhalation composition was loaded into No. 3 HPMC capsules in a loading amount of 25 mg.

[0216] The aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products was measured using a new generation impactor (NGI) at a flow rate of 60 L / min. Specific data are shown in Table 12:

[0217] Table 12 APSD indicators of samples from Example 12 and commercial products

[0218]

[0219] Compared with Example 3, after the mixing speed of (ii) was reduced from 200 rpm to 150 rpm, the APSD indicators of the sample were slightly lower than those of the commercial product (the values were lower by more than 15%), which once again verified that the mixing speed is preferably not less than 200 rpm.

[0220] Comparative Example 1

[0221] This comparative example provides a dry powder inhalation composition, the composition and preparation method of which are the same as those in Example 1, except that: the mixing process in step (i) is replaced by mixing in a three-dimensional mixer at a speed of 44 rpm for 30 minutes; and the mixing process in step (ii) is replaced by mixing in a three-dimensional mixer at a speed of 44 rpm for 60 minutes.

[0222] The aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products was measured using a new generation impactor (NGI) at a flow rate of 60 L / min. Specific data are shown in Table 13:

[0223] Table 13 APSD indicators of the sample of Comparative Example 1 and commercial products

[0224]

[0225] For the sample of Comparative Example 1, both the FPD and FPF values are lower than those of the commercial products (by more than 15% in value), and are significantly lower than the samples prepared by high-shear mixing in the examples of this application.

[0226] Comparative Example 2

[0227] This comparative example provides a dry powder inhalation composition, which has the same composition and preparation method as Example 1. The main difference lies in that: the mixing process in step (ii) is replaced by mixing in a three-dimensional mixer at a rotation speed of 44 rpm for 60 minutes.

[0228] Using a Next Generation Impactor (NGI), the aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products was measured at a flow rate of 60 L / min. The specific data are shown in Table 14:

[0229] Table 14 APSD indicators of the sample of Comparative Example 2 and commercial products

[0230]

[0231] For the sample of Comparative Example 2, both the FPD and FPF values are lower than those of the commercial products (by more than 15% in value), and are significantly lower than the samples prepared by high-shear mixing in the examples of this application.

[0232] Comparative Example 3

[0233] This comparative example provides a dry powder inhalation composition, which has the same composition and preparation method as Example 1. The main difference lies in that: the mixing process in step (i) is replaced by mixing in a three-dimensional mixer at a rotation speed of 44 rpm for 30 minutes.

[0234] Using a Next Generation Impactor (NGI), the aerodynamic particle size distribution (APSD) of the above capsule samples and commercial products was measured at a flow rate of 60 L / min. The specific data are shown in Table 15:

[0235] Table 15 APSD indicators of the sample of Comparative Example 3 and commercial products

[0236]

[0237] For the sample of Comparative Example 3, both the FPD and FPF values are lower than those of the commercial products (by more than 15% in value), and are significantly lower than the samples prepared by high-shear mixing in the examples of this application.

[0238] Test Example 1

[0239] The samples of Example 1 and the commercial products were placed under accelerated conditions (40°C ± 2°C / RH 75% ± 5%) and long-term conditions (25°C ± 2°C / RH 60% ± 5%) for 2 months, and the aerodynamic particle size distribution (APSD) of the samples and the commercial products was measured at a flow rate of 60 L / min. The specific data are shown in Tables 16 and 17:

[0240] Table 16 APSD indicators of the samples of Example 1 and the commercial products after 2 months of acceleration

[0241]

[0242] Table 17 APSD indicators of the samples of Example 1 and the commercial products after 2 months of long-term storage

[0243]

[0244] All the APSD indicators of the samples of Example 1 after 2 months of acceleration and 2 months of long-term storage are comparable to those of the commercial products (the numerical difference is within ±15%), indicating that the samples have good stability.

[0245] Test Example 2

[0246] The samples of Example 2 and the commercial products were placed under accelerated conditions (40°C ± 2°C / RH 75% ± 5%) and long-term conditions (25°C ± 2°C / RH 60% ± 5%) for 2 months, and the aerodynamic particle size distribution (APSD) of the samples and the commercial products was measured at a flow rate of 60 L / min. The specific data are shown in Tables 18 and 19:

[0247] Table 18 APSD indicators of the samples of Example 2 and the commercial products after 2 months of acceleration

[0248]

[0249] Table 19 APSD indicators of the samples of Example 2 and the commercial products after 2 months of long-term storage

[0250]

[0251] All the APSD indicators of the samples of Example 2 after 2 months of acceleration and 2 months of long-term storage are comparable to those of the commercial products (the numerical difference is within ±15%), indicating that the samples have good stability.

[0252] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as falling within the scope described in this specification.

[0253] The above-described embodiments merely represent several implementation manners of the present application, facilitating a specific and detailed understanding of the technical solution of the present application. However, it should not be construed as a limitation on the scope of patent protection of the application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can be made, and these all fall within the protection scope of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning, or limited experiments based on the technical solution provided by the present application are all within the protection scope of the appended claims of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A method for preparing a dry powder inhalation composition, characterized in that, The dry powder inhalation composition comprises a substrate and an active ingredient, and the preparation method comprises the following steps: Performing a first high-shear mixing on the substrate to prepare an intermediate material; Performing a second high-shear mixing on the intermediate material and the active ingredient; Wherein, the rotation speed of the first high-shear mixing ≥ 150 rpm; The rotation speed of the second high-shear mixing ≥ 150 rpm.

2. The preparation method of the dry powder inhalation composition according to claim 1, wherein The rotation speed of the first high-shear mixing is 150 rpm to 850 rpm, and the time is 5 min to 60 min.

3. The preparation method of the dry powder inhalation composition according to claim 2, wherein, The rotation speed of the first high-shear mixing is 200 rpm to 800 rpm.

4. The method for preparing the dry powder inhalation composition according to claim 1, wherein, The rotation speed of the second high-shear mixing is 150 rpm to 850 rpm, and the time is 5 min to 60 min.

5. The method for preparing the dry powder inhalation composition according to claim 4, characterized in that, The rotation speed of the second high-shear mixing is 200 rpm to 800 rpm.

6. The preparation method of the dry powder inhalation composition according to any one of claims 1 to 5, characterized in that, The substrate comprises lactose; Optionally, the lactose is in the form of a hydrate, and further optionally, the lactose is lactose monohydrate; Optionally, the substrate further comprises magnesium stearate.

7. The preparation method of the dry powder inhalation composition according to claim 6, characterized in that, In the dry powder inhalation composition, the mass percentage of lactose monohydrate ≥ 90%, and the mass percentage of magnesium stearate is 0 to 0.2%.

8. The preparation method of the dry powder inhalation composition according to any one of claims 1 to 5, characterized in that, The active ingredient has at least one of the following characteristics: (1) The active ingredient comprises one or more of an anticholinergic drug, a long-acting β2-agonist, and an inhaled corticosteroid; (2) The particle size distribution of the active ingredient is D 50 ≤ 5 μm, and D 90 ≤ 10 μm.

9. The dry powder inhalation composition prepared by the preparation method according to any one of claims 1 to 8.

10. A drug delivery system, characterized in that, Comprising a dry powder inhalation device and the dry powder inhalation composition according to claim 9 accommodated in the dry powder inhalation device.

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