A capsule type inhalation powder and a method for preparing the same

Abstract

The application belongs to the technical field of biological medicine, and relates to a medicine preparation, in particular to a capsule type inhalation powder aerosol and a preparation method thereof. The active ingredient of the capsule type inhalation powder aerosol is glycopyrronium bromide, the content of the glycopyrronium bromide in each capsule in terms of glycopyrronium is not higher than 20.0 mu g, and the FPF in the air dynamic characteristics is 50.0-75.0%. The capsule type inhalation powder aerosol provided by the application can significantly improve the drug safety on the premise of ensuring the drug efficacy.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to pharmaceutical preparations, specifically to a capsule-type inhaled powder and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Glycerone bromide is a quaternary ammonium long-acting anticholinergic drug that specifically binds to and inhibits M3 acetylcholine receptors distributed in bronchial smooth muscle, thereby exerting a bronchodilatory pharmacological effect. Currently, commercially available glycopyrronium bromide-containing inhaled powder products mainly include the single-component glycopyrronium bromide inhaled powder (Xirun) manufactured by Novartis, Switzerland. ® Compound Indidatarbutin Bromide Inhalation Powder (Jerrun) ® ) and three-way indagamoxol inhalation powder (Enzorun) ® Of the three products, glycopyrronium bromide contains 63 μg in each capsule (50 μg as glycopyrronium), and the dosage is one puff once daily.

[0004] Inhaled powder inhalers offer advantages for treating COPD, including rapid onset of action, high local drug concentration, and relatively few systemic side effects. However, inhaling higher doses of glycopyrronium bromide increases the probability and risk of adverse clinical reactions, such as dry mouth, urinary retention, and adverse reactions related to local tolerance, including pharyngeal irritation and nasopharyngitis. According to the product information leaflet, even at the recommended dose, this product can cause very common (≥1 / 10) upper respiratory tract infection symptoms and common (≥1 / 100 to <1 / 10) nasopharyngitis, sinusitis, and urinary tract infections. In addition, some neurological disorders such as dizziness and headache, eye diseases such as glaucoma, gastrointestinal diseases such as indigestion and dry mouth, and kidney and urinary system diseases such as bladder obstruction and urinary retention are common or occasional (≥1 / 1000 to <1 / 100) adverse reactions listed in the product information leaflet.

[0005] Due to their highly efficient nebulization, inhaled powder medications readily diffuse into the peripheral lung areas, leading to rapid dissolution and absorption into the bloodstream. This is especially true for micronized medications, where the extremely fine powder tends to deposit in the terminal bronchioles and alveoli. This often results in very high Cmax and systemic exposure in the pharmacokinetic parameters, increasing the likelihood of systemic adverse reactions. Furthermore, inhaled powder medications may experience incomplete dissociation, leaving a significant amount of the active ingredient trapped in the throat and other areas, causing pharyngeal irritation and inflammation. This is a major cause of adverse reactions related to local tolerance. Summary of the Invention

[0006] Inhaled powder inhalers refer to formulations in which solid, micronized drug substances, alone or mixed with a suitable carrier, are delivered to the lungs via a specialized dry powder inhaler, in capsule, blister, or multi-dose reservoir form. The efficacy and incidence of adverse drug reactions of inhaled powder inhalers are closely related to the drug dosage and the deposition site in the respiratory tract. Generally, drug particles with an aerodynamic diameter greater than 5 μm are primarily deposited in the pharynx due to inertial impaction and can reach the gastrointestinal tract with swallowing, where they are absorbed into the systemic circulation. Particles with a diameter between 0.5 μm and 5 μm settle into the lungs due to gravity, with particles of 3–5 μm mainly distributed in the central lung area (such as the trachea and bronchi), while particles smaller than 3 μm can be delivered more deeply to the peripheral lung area (such as the respiratory bronchioles, alveolar ducts, and alveolar sacs). Drugs with a diameter less than 5 μm are considered inhalable doses and can bind to receptors in the lungs to produce therapeutic effects. In in vitro studies of inhaled powder aerosols, drug particles with an aerodynamic diameter of less than 5 μm are typically defined as fine particle dose (FPD) to characterize the quality of drug deposition in the lungs, and the ratio of fine particle dose to delivered dose is defined as fine particle fraction (FPF) to characterize the effective deposition efficiency of the drug.

[0007] According to literature, M3 receptors with bronchodilatory effects are mainly located on airway smooth muscle, with the highest distribution in the central region of the lungs. The product involved in this invention is a bronchodilator. According to the aforementioned drug delivery theory, delivering the drug to the trachea, bronchi, and secondary bronchi is beneficial for efficacy. However, excessive delivery to the pharynx or other areas can easily lead to adverse reactions related to local tolerance, such as pharyngeal irritation and nasopharyngitis. Excessive delivery to the terminal bronchioles, alveolar ducts, and alveoli can cause the drug to enter the bloodstream rapidly, thereby increasing C... maxThis increases systemic exposure and the incidence of adverse systemic reactions. The purpose of this invention is to provide a capsule-type inhaled powder and its preparation method. Through the technical means of this invention, the drug is delivered to effective sites such as the trachea, bronchi, and secondary bronchi, ensuring efficacy while reducing adverse drug reactions. To achieve the above objective, the glycopyrronium content in each capsule of this invention is significantly lower than that in commercially available products. Furthermore, through the preparation method of this invention, the product's effective powder concentration (FPF) is controlled within a certain range, ensuring efficacy while reducing adverse drug reactions and improving medication safety.

[0008] Specifically, in order to achieve the above objectives, the technical solution of the present invention is as follows:

[0009] On the one hand, there is a capsule-type inhaled powder, the active ingredient of which is glycopyrronium bromide, the content of glycopyrronium bromide in each capsule is not higher than 20.0 μg, and the fine particulate fraction (FPF) in the aerodynamic characteristics is 50.0~75.0%.

[0010] The present invention shows that FPF is the key factor affecting the efficacy and safety of low-dose glycopyrronium bromide powder inhaler. When the content of glycopyrronium bromide in each capsule is not higher than 20.0 μg and the FPF is 50.0~75.0%, the efficacy and safety of glycopyrronium bromide powder inhaler can be guaranteed.

[0011] On the other hand, a method for preparing the above-mentioned capsule-type inhaled powder includes the following steps:

[0012] The active ingredient, dispersant, and carrier are provided according to the prescription, and the carrier is divided into large-particle-size carrier and small-particle-size carrier;

[0013] A carrier complex is obtained by mixing a portion of the dispersing agent with a portion of the small-particle-size carrier.

[0014] Mix the carrier complex with the active ingredient and the remaining prescription ingredients thoroughly.

[0015] As mentioned earlier, the effective powder concentration (FPF) is crucial to the efficacy and safety of low-dose glycopyrronium bromide powder inhaler. The dosage of this invention is significantly lower than that of marketed products; if the FPF is too low, efficacy cannot be guaranteed; if the FPF is too high, there is a risk of increased systemic adverse reactions. Ensuring the FPF of low-dose glycopyrronium bromide powder inhaler is a challenge in this field, thus requiring adjustments to the preparation method or process to guarantee a reasonable FPF range.

[0016] Further research has shown that the mixing method is an important factor affecting the FPF of low-dose glycopyrronium bromide powder inhalers. When a portion of the dispersing agent is mixed with a portion of the small-particle-size carrier to obtain a carrier complex, mixing this carrier complex with the remaining formulation ingredients can significantly improve the FPF, thereby ensuring that the FPF is not less than 50.0% when the content of glycopyrronium bromide in each capsule is not higher than 20.0 μg.

[0017] The beneficial effects of this invention are as follows:

[0018] 1. This invention reduces the incidence of adverse reactions and significantly improves medication safety by simultaneously adjusting the content of glycopyrronium bromide and FPF while ensuring efficacy.

[0019] 2. By adjusting the mixing method, this invention overcomes the problem of mixing uniformity in extremely low drug content, ensuring the FPF of low-dose glycopyrronium bromide powder inhaler, thereby guaranteeing its efficacy and safety reliability. Detailed Implementation

[0020] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0021] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0022] Given the high incidence of adverse reactions associated with current glycopyrronium bromide powder inhalers, this invention proposes a capsule-type inhaled powder inhaler and its preparation method.

[0023] In one typical embodiment of the present invention, a capsule-type inhaled powder is provided, wherein the active ingredient is glycopyrronium bromide, the content of glycopyrronium bromide in each capsule is not higher than 20.0 μg, and the aerodynamic characteristics have an FPF of 50.0~75.0%.

[0024] The dosage of the capsule-type inhaled powder of the present invention is one capsule per application.

[0025] The content of glycopyrronium bromide, calculated as glycopyrronium, in each capsule can be 5.0~20.0 μg, 5.0~10.0 μg, 10.0~20.0 μg, 5.0~15.0 μg, 15.0~20.0 μg, 6.0~19.0 μg, 6.0~9.0 μg, 9.0~19.0 μg, 6.0~11.0 μg, 11.0~19.0 μg, 7.0~18.0 μg, 7.0~13.0 μg, 13.0~18.0 μg. The dosage ranges are 0 μg, 7.0~17.0 μg, 7.0~14.0 μg, 14.0~17.0 μg, 5.0~6.0 μg, 6.0~7.0 μg, 7.0~8.0 μg, 9.0~10.0 μg, 10.0~11.0 μg, 11.0~12.0 μg, 13.0~14.0 μg, 15.0~16.0 μg, 16.0~17.0 μg, 17.0~18.0 μg, 19.0~20.0 μg, etc. Preferably, it is 5.0~20.0 μg, more preferably 6.0~19.0 μg, and even more preferably 13.0~18.0 μg.

[0026] The FPF can be 50.0~55.0%, 55.0~75.0%, 50.0~60.0%, 60.0~75.0%, 50.0~65.0%, 65.0~75.0%, 55.0~70.0%, 70.0~75.0%, 55.0~72.0%, 50.0~59.0%, 59.0~69.0%, 69.0~75.0%, etc. Preferably, it is 55.0~70.0%, more preferably 55.0~72.0%, and even more preferably 59.0~69.0%.

[0027] This invention demonstrates that when using a new generation cascade impactor (NGI) to study the in vitro aerodynamic properties of a product, a higher product FPF, especially a higher deposition rate at the 5-MoC strata, results in a higher in vivo pharmacokinetic parameter C. max The higher the value, the better. max Excessive FPF often increases the risk of systemic adverse reactions; the lower the product's FPF, the lower the C in the body. max A lower FPF generally indicates better product safety, but excessively low FPF reduces drug deposition at the effective site, potentially leading to decreased efficacy. In some embodiments, when the FPF in the aerodynamic particle size distribution (APSD) of the product is 77% and the MOC stratum deposition is 4.4 μg, the pharmacokinetic parameter C of the self-developed formulation in animals is... maxThe significantly higher FPF of the self-developed formulation compared to the marketed formulation suggests that the self-developed formulation has a higher systemic exposure. Higher systemic exposure increases the risk of clinical side effects of inhaled drugs. Therefore, the FPF of the self-developed formulation should not exceed 77%, and correspondingly, the 5-MoC deposition amount should be less than 4.4 μg. In some embodiments, when the FPF in the aerodynamic particle size distribution (APSD) of the product is 40% and the 5-MoC stratum deposition amount is 1.1 μg, the concentration of the self-developed formulation at the effective sites (main trachea and bronchi) is already lower than that of the marketed formulation, suggesting that the efficacy of the self-developed formulation may be worse than that of the marketed formulation. Therefore, the FPF of the self-developed formulation should not be less than 40%, and correspondingly, the 5-MoC deposition amount should be higher than 1.1 μg.

[0028] Studies have shown that when the deposition amount of the 5~MOC layer is 1.3 μg~4.1 μg, it can ensure C max This effectively reduces the drug's concentration and provides good therapeutic efficacy. The deposition amount of the 5-MOC layer can be 1.3 μg~2.0 μg, 2.0 μg~3.0 μg, 3.0 μg~4.1 μg, etc. Preferably, it is 2.0 μg~3.5 μg, and more preferably, it is 2.0 μg~3.0 μg.

[0029] In some embodiments, the content uniformity is RSD≤5%, preferably RSD≤3%, and more preferably RSD≤2%.

[0030] In some embodiments, the content of glycopyrronium bromide is 0.05 to 0.20% of the total weight of the powder aerosol formulation.

[0031] In some embodiments, the pharmaceutical excipients used include a carrier, which is one or more of lactose, dextran, mannitol, xylitol, phosphatidylcholine, and cholesterol.

[0032] In one or more embodiments, the carrier is classified into large-particle-size carriers and small-particle-size carriers according to its particle size.

[0033] Specifically, the particle size distribution range of the large-particle-size carrier is: D 10 The diameter is 4~10μm, D 50 30 ~ 60 μm, D 90 The size is 80~150 μm.

[0034] Specifically, the particle size distribution range of the small-diameter carrier is: D 10 The range is 0.4~1.2μm, D 50 The range is 1.5~4.7μm, D 90 The range is 5.0~20.0μm.

[0035] Specifically, the content of small-particle-size carriers is 2.0 to 6.0% of the total weight of the powder aerosol formulation.

[0036] In some embodiments, the pharmaceutical excipients used include dispersing agents, which are one or more of sodium stearate, magnesium stearate, calcium stearate, and colloidal silica.

[0037] In some embodiments, the content of the dispersing agent is 0.1 to 0.5% of the total weight of the powder atomizer formulation.

[0038] Specifically, the particle size distribution range of the dispersing aid is: D 10 The range is 2.2~4.2μm, D 50 The range is 7.2~11.5μm, D 90 The size is 16~30 μm.

[0039] In some embodiments, the pharmaceutical excipient comprises an aliphatic polyester. In one or more embodiments, the aliphatic polyester content is 0.08-0.15% of the total weight of the powder inhaler formulation. The aliphatic polyester may be polyglycolic acid and / or polycaprolactone. When the aliphatic polyester is polyglycolic acid, the content is preferably 0.08-0.12% of the total weight of the powder inhaler formulation. When the aliphatic polyester is polycaprolactone, the content is preferably 0.08-0.15% of the total weight of the powder inhaler formulation.

[0040] When the aliphatic polyester is polyglycolic acid, the particle size distribution range is: D 10 The diameter is 0.5~0.7μm, D 50 The diameter is 1.2~2.0μm, D 90 The particle size distribution ranges from 3.0 to 5.0 μm; when the aliphatic polyester is polycaprolactone, the particle size distribution range is: D 10 The thickness is 1.0~1.5μm, D 50 The diameter is 2.5~3.5 μm, D 90 The thickness is 5.0~7.0μm.

[0041] In some embodiments, the active ingredient further includes one or more of formoterol, indacaterol, salmeterol, and vilanterol. The concentration of these active ingredients in the capsule-type inhalation powder is 0.06% to 0.15% (mass percentage).

[0042] In some embodiments, the active ingredient further includes at least one or more of budesonide, ciroxonide, and triamcinolone. The concentration of these active ingredients in the capsule-type inhalation powder is 1.0–5.0% (by mass).

[0043] Another embodiment of the present invention provides a method for preparing the above-mentioned capsule-type inhaled powder, comprising the following steps:

[0044] The active ingredient, dispersant, and carrier are provided according to the prescription, and the carrier is divided into large-particle-size carrier and small-particle-size carrier;

[0045] A carrier complex is obtained by mixing a portion of the dispersing agent with a portion of the small-particle-size carrier.

[0046] Mix the carrier complex with the active ingredient and the remaining prescription ingredients thoroughly.

[0047] Specifically, the carrier is one or more of lactose, dextran, mannitol, xylitol, phosphatidylcholine, and cholesterol.

[0048] Specifically, the particle size distribution range of the large-particle-size carrier is: D 10 The diameter is 4~10μm, D 50 30 ~ 60 μm, D 90 The size is 80~150μm.

[0049] Specifically, the particle size distribution range of the small-diameter carrier is: D 10 The range is 0.4~1.2μm, D 50 The range is 1.5~4.7μm, D 90 The range is 5.0~20.0μm.

[0050] Specifically, the content of small-particle-size carriers is 2.0 to 6.0% of the total weight of the powder aerosol formulation.

[0051] Specifically, the dispersing agent is one or more of sodium stearate, magnesium stearate, calcium stearate, and colloidal silica.

[0052] Specifically, the particle size distribution range of the dispersing aid is: D 10 The range is 2.2~4.2μm, D 50 The range is 7.2~11.5μm, D 90 The size is 16~30 μm.

[0053] In some embodiments, all dispersing agents and a portion of small-particle-size carriers are mixed at a weight ratio of 1:5 to 20, preferably 1:5 to 10, more preferably 1:10 to 20, more preferably 1:10 to 15, and more preferably 1:15 to 20. This addition significantly improves the uniformity of powder atomization content and delivery stability.

[0054] In some embodiments, during the process of mixing a portion of the dispersing agent with a portion of the small-particle-size carrier to obtain the carrier composite, the amount of the dispersing agent added is 1 / 8 to 3 / 5 of the total weight of the dispersing agent. Studies have shown that the amount of the dispersing agent added affects the stratified deposition amount of 5-MOC. When the amount of the dispersing agent added is 1 / 8 to 1 / 4 of the total weight of the dispersing agent, the stratified deposition amount of 5-MOC can be guaranteed to be 3.0 μg to 4.1 μg; when the amount of the dispersing agent added is 1 / 4 to 1 / 2 of the total weight of the dispersing agent, the stratified deposition amount of 5-MOC can be guaranteed to be 2.1 μg to 3.0 μg; and when the amount of the dispersing agent added is 1 / 2 to 3 / 5 of the total weight of the dispersing agent, the stratified deposition amount of 5-MOC can be guaranteed to be 1.3 μg to 2.1 μg.

[0055] The method of uniformly mixing the carrier complex with the active ingredient and the remaining prescription ingredients as described in this invention can be carried out by conventional mixing methods, which can also ensure the efficacy.

[0056] In some embodiments, the carrier complex is mixed with the active ingredient, then micronized to obtain active ingredient intermediate I, which is then uniformly mixed with the remaining formulation ingredients. This method is beneficial for improving the FPF of capsule-type inhaled powder.

[0057] Specifically, air jet milling is used for micronization, typically employing an air jet mill. The parameters for air jet milling are: feed pressure of 3~10 bar, milling pressure of 2~9 bar, and feed speed of 5~30 rpm.

[0058] The active ingredient intermediate I is mixed evenly with the remaining prescription ingredients, which can be done using conventional mixing methods.

[0059] In one or more embodiments, active ingredient intermediate I is uniformly mixed with a portion of a large-particle-size carrier to obtain active ingredient intermediate II, and active ingredient intermediate II is then uniformly mixed with the remaining formulation ingredients. Studies have shown that this method can further improve the content uniformity and delivery stability of capsule-type inhaled powder.

[0060] Specifically, the weight ratio of active ingredient intermediate I to a portion of the large-particle-size carrier is 1:1 to 5. Studies have shown that increasing the amount of large-particle-size carrier is beneficial to improving the uniformity of product content and delivery stability, therefore, a ratio of 1:2 to 5 is preferred, further preferred is 1:3 to 5, and even more preferred is 1:4 to 5.

[0061] Specifically, a three-dimensional motion mixer is used to mix active ingredient intermediate I with a portion of large-particle-size carriers to obtain active ingredient intermediate II. More specifically, the mixing speed is 30~90Hz and the mixing time is 10~60min.

[0062] Specifically, a three-dimensional motion mixer is used to mix the remaining dispersant and the remaining large-particle-size carrier in the formulation to obtain a dispersant mixture.

[0063] In one or more embodiments, the active ingredient intermediate II is mixed uniformly with all remaining formulation ingredients using a high-speed shear mixing device. The mixing linear velocity is 3-12 m / s, and the mixing time is preferably 3-9 min. High-speed shear mixing is performed using a high-shear mixing device such as GEA.

[0064] More specifically, its preparation process is as follows:

[0065] (1) A carrier complex is obtained by mixing a portion of the dispersing agent with a portion of the small-particle-size carrier;

[0066] (2) The carrier complex, active ingredients, and remaining prescription ingredients are mixed evenly using conventional mixing methods.

[0067] The selection of materials in this preparation process is the same as described above.

[0068] More specifically, its preparation process is as follows:

[0069] (1) A carrier complex is obtained by mixing a portion of the dispersing agent with a portion of the small-particle-size carrier;

[0070] (2) The carrier complex is mixed with the active ingredient and then micronized to obtain active ingredient intermediate I;

[0071] (3) Mix the active ingredient intermediate I with the remaining prescription ingredients evenly using conventional mixing methods.

[0072] The selection of materials in this preparation process is the same as described above.

[0073] More specifically, its preparation process is as follows:

[0074] (1) A carrier complex is obtained by mixing a portion of the dispersing agent with a portion of the small-particle-size carrier;

[0075] (2) The carrier complex is mixed with the active ingredient and then micronized to obtain active ingredient intermediate I;

[0076] (3) Mix the active ingredient intermediate I with a portion of the large particle size carrier evenly to obtain the active ingredient intermediate II;

[0077] (4) Mix the active ingredient intermediate II with the remaining prescription ingredients evenly.

[0078] The selection of materials in this preparation process is the same as described above.

[0079] More specifically, its preparation process is as follows:

[0080] (1) A carrier complex is obtained by mixing a portion of the dispersing agent with a portion of the small-particle-size carrier;

[0081] (2) The carrier complex is mixed with the active ingredient and then micronized to obtain active ingredient intermediate I;

[0082] (3) Mix the active ingredient intermediate I with a portion of the large particle size carrier evenly to obtain the active ingredient intermediate II;

[0083] (4) Mix the remaining amount of dispersant and the remaining amount of large particle size carrier to obtain a dispersant mixture;

[0084] (5) Mix the active ingredient intermediate II with the remaining amount of small particle size carrier and dispersant mixture evenly.

[0085] The conventional mixing method can be performed using high-shear mixing equipment and / or a three-dimensional motion mixer.

[0086] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific experimental examples.

[0087] Experimental Examples 1-5: Screening Tests for Crude Lactose Particle Size Distribution

[0088] Test materials and methods

[0089] Use the following test materials:

[0090] Micronized glycopyrronium bromide (D 90 <5μm)

[0091] Crude lactose 1 (D 90 (83μm)

[0092] Crude lactose 2 (D 90 (126μm)

[0093] Crude lactose 3 (D) 90 (148μm)

[0094] Crude lactose 4 (D 90 (175μm)

[0095] Crude lactose 5 (D 90 (225μm)

[0096] Information on these test materials is listed in Table 1.

[0097] Table 1. Test Material Information

[0098] Test materials <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Micronized glycopyrronium bromide 0.72 2.10 4.25 crude lactose 1 7 35 83 Crude lactose 2 9 55 126 crude lactose 3 14 63 148 crude lactose 4 50 110 175 crude lactose 5 55 135 225

[0099] Inhalation powder can be prepared by the following method:

[0100] 1. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: 1 / 3 crude lactose (covering all mixing blades); 1 / 2 micronized glycopyrronium bromide; 1 / 3 crude lactose; remaining micronized glycopyrronium bromide; remaining crude lactose. After adding the materials, close the sealing cap.

[0101] 2. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0102] 3. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0103] 4. Pack the filled capsules in double aluminum packaging.

[0104] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 2.

[0105] Table 2 Results of product performance evaluation indicators for Experiment Examples 1-5

[0106]

[0107] Data from Examples 1-5 show that the formulations performed poorly in terms of content uniformity and delivery stability. However, overall, the formulation in Example 2 showed slightly better performance. Therefore, crude lactose 2 was selected as the preferred crude lactose for the next stage of testing.

[0108] Experiments 6-8: Screening Tests for Crude Lactose Particle Size Span

[0109] Test materials and methods

[0110] Use the following test materials:

[0111] Micronized glycopyrronium bromide (D 90 <5μm)

[0112] Crude lactose 2 (Span: 2.1)

[0113] Crude lactose 6 (Span: 2.9)

[0114] Crude lactose 7 (Span: 3.7)

[0115] Information on these test materials is listed in Table 3.

[0116] Table 3. Test Material Information for Examples 6-8

[0117] Test materials <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Span Micronized glycopyrronium bromide 0.72 2.10 4.25 1.7 Crude lactose 2 9 55 126 2.1 Crude lactose 6 5 42 126 2.9 Crude lactose 7 3 34 128 3.7

[0118] The inhaled powder preparation methods described in Examples 1-5 were used to test the content uniformity, delivery stability, and FPF of the obtained products. The specific test results are shown in Table 4.

[0119] Table 4. Results of product performance evaluation indicators for Test Examples 6-8

[0120]

[0121] Data from Experiments 6-8 show that Experiment 6 and Experiment 2 were completely replicated, and the results showed good repeatability. The formulation obtained in Experiment 7 performed better than the formulations obtained in other experiments in terms of content uniformity and delivery stability. Although the formulation obtained in Experiment 8 had the highest FPF, its delivery stability was poor. Therefore, lactose from Experiment 7, i.e. crude lactose 6, was selected as the preferred crude lactose for the next experiment.

[0122] Experimental Examples 9-11: Investigation of the effects of using fine lactose and micronized glycopyrronium bromide alone.

[0123] Test materials and methods

[0124] Use the following test materials:

[0125] Micronized glycopyrronium bromide (D 90 <5μm)

[0126] Fine lactose 1 (D) 90 (7.39μm)

[0127] Fine lactose 2 (D) 90 (20μm)

[0128] Fine lactose 3 (D) 90 : 32μm)

[0129] Information on these test materials is listed in Table 5.

[0130] Table 5. Test material information for Test Examples 9-11

[0131] <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Micronized glycopyrronium bromide 0.72 2.10 4.25 Fine lactose 1 0.63 2.86 7.39 Fine lactose 2 1.5 8 20 Fine lactose 3 2.7 13 32

[0132] Inhalation powder can be prepared by the following method:

[0133] 1. Place at least 5 alternating layers of fine lactose and micronized glycopyrronium bromide in a Turbula 3D motion mixer.

[0134] 2. Set the mixing speed to 30 rpm and the mixing time to 30 minutes.

[0135] 3. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0136] 4. Pack the filled capsules in double aluminum packaging.

[0137] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 6.

[0138] Table 6 Results of product performance evaluation indicators for Test Examples 9-11

[0139]

[0140] Data from Examples 9-11 show that for formulations containing only 0.17% w / w glycopyrronium bromide, the overall mixture homogeneity is very poor when using a low-shear mixing method such as a three-dimensional motion mixer. Therefore, the content homogeneity and delivery stability of the formulation are no longer tested.

[0141] Conclusion: It is difficult to achieve uniform mixing of the total mixture when using fine lactose and micronized glycopyrronium bromide raw materials alone.

[0142] Experimental Examples 12-14:

[0143] The preparation method is as follows:

[0144] 1. Prepare a premix of glycopyrronium bromide and fine lactose according to the methods and materials in Experiment Examples 9-11.

[0145] 2. Use an air jet mill, set the grinding pressure to 3.0 bar and the feeding speed to 80 rpm, to micronize the above premix.

[0146] 3. Test the mixing uniformity of the micronized aggregate obtained above.

[0147] 4. Prepare the above micronized mixture into a spherical intermediate product.

[0148] 5. Fill the above-mentioned spherical intermediate product into the reservoir-type inhalation device.

[0149] The performance of the above products was evaluated, and the evaluation indicators included the uniformity of the total mixture, delivery stability, and FPF. The specific test results are listed in Table 7.

[0150] Table 7 Results of product performance evaluation indicators for Test Examples 12-14

[0151]

[0152] Data from Experiments 12-14 show that the overall mixture obtained by co-micronizing lactose and raw materials has better uniformity than that obtained in Experiments 9-11, but the product delivery stability is worse.

[0153] Conclusion: When fine lactose and glycopyrronium bromide are mixed alone and the mixture is prepared into a spherical intermediate product and filled into a reservoir-type inhalation device, the product delivery stability is poor.

[0154] Experimental Examples 15-17: Experimental Study on the Mixture of Coarse and Fine Lactose with Micronized Glyceryl Bromide

[0155] Test materials and methods

[0156] Use the following test materials:

[0157] Micronized glycopyrronium bromide (D 90 <5μm)

[0158] Crude lactose 6 (D) 90 (126μm)

[0159] Fine lactose 1 (D) 90 (7.39μm)

[0160] Fine lactose 2 (D) 90 (20μm)

[0161] Fine lactose 3 (D) 90 : 32μm)

[0162] Inhalation powder can be prepared by the following method:

[0163] 1. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 crude lactose (covering all mixing blades); approximately 1 / 2 fine lactose; approximately 1 / 2 micronized glycopyrronium bromide raw material; approximately 1 / 3 crude lactose; remaining micronized glycopyrronium bromide raw material; remaining fine lactose; remaining crude lactose. After adding the materials, close the sealing cap.

[0164] 2. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0165] 3. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0166] 4. Pack the filled capsules in double aluminum packaging.

[0167] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 8.

[0168] Table 8 Results of product performance evaluation indicators in Test Examples 15-17

[0169]

[0170] Data from Examples 15-17 show that the uniformity of the final mixture obtained by combining coarse and fine lactose with micronized glycopyrronium bromide is significantly better than that obtained by using only fine lactose and glycopyrronium bromide in Examples 9-11, and slightly better than that obtained by using only coarse lactose and glycopyrronium bromide in Examples 6-8. Furthermore, the fractional powder per unit area (FPF) of the formulations in Examples 15-17 is significantly higher than that in Examples 6-8. In summary, the method of combining coarse and fine lactose with micronized glycopyrronium bromide is superior to using only coarse lactose or only fine lactose with glycopyrronium bromide. Since the formulation obtained in Experiment 15 exhibits the best content uniformity and the highest FPF, fine lactose (specifically, fine lactose 1) from Experiment 15 is selected as the preferred fine lactose for the next stage of experiments.

[0171] The product exhibits a significant improvement in content uniformity and delivery stability. Therefore, the refined lactose in Experiment 15, namely refined lactose 1, was selected as the preferred refined lactose for the next stage of testing.

[0172] Experimental Examples 18-21: Experiments to investigate the ratio of refined lactose

[0173] Test materials and methods

[0174] Use the following test materials:

[0175] Micronized glycopyrronium bromide (D 90 <5μm)

[0176] Crude lactose 6 (D) 90 (126μm)

[0177] Fine lactose 1 (D) 90 (7.39μm)

[0178] Inhaled powder formulations were prepared using the methods described in Examples 15-17. The performance of these products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 9.

[0179] Table 9 Results of product performance evaluation indicators for Test Examples 18-21

[0180]

[0181] Data from Experiments 18-21 show that the results of Experiments 15 and 18 exhibit good repeatability. When the proportion of refined lactose is in the range of 2%-6% (w / w), adjusting the proportion has little impact on product content uniformity and delivery stability, but it can significantly affect FPF. When the proportion of refined lactose is 8%, product content uniformity, delivery stability, and FPF deteriorate. In the initial stage of formulation and process investigation, a refined lactose proportion of 4.0% (w / w) is tentatively selected for the next stage of experiments.

[0182] Experimental Examples 22-25: Investigation of the Effect of Adding Magnesium Stearate on Mixtures

[0183] Test materials and methods

[0184] Use the following test materials:

[0185] Micronized glycopyrronium bromide (D 90 <5μm)

[0186] Crude lactose 6 (D) 90 (126μm)

[0187] Fine lactose 1 (D) 90 (7.39μm)

[0188] Magnesium stearate (D) 90 :23μm)

[0189] Inhalation powder can be prepared by the following method:

[0190] 1. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 crude lactose (covering all agitator blades); approximately 1 / 2 magnesium stearate; approximately 1 / 2 fine lactose; approximately 1 / 2 micronized glycopyrronium bromide raw material; approximately 1 / 3 crude lactose; remaining micronized glycopyrronium bromide raw material; remaining fine lactose; remaining magnesium stearate; remaining crude lactose. After adding the materials, close the sealing cap.

[0191] 2. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0192] 3. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0193] 4. Pack the filled capsules in double aluminum packaging.

[0194] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 10.

[0195] Table 10 Results of product performance evaluation indicators for Test Examples 22-25

[0196]

[0197] Data from Experiments 22-25 show that the product's Fastest Product Flow (FPF) gradually increases with the increase in the mass ratio of magnesium stearate. However, unexpectedly, the addition of magnesium stearate led to a decrease in the product's content uniformity and delivery stability. Given that the addition of magnesium stearate significantly improves the product's FPF, the addition of 0.5% w / w magnesium stearate will be considered in subsequent experiments.

[0198] Investigation of the impact of hybridization process on product performance

[0199] Test materials and methods

[0200] Use the following test materials:

[0201] Micronized glycopyrronium bromide (D 90 <5μm)

[0202] Crude lactose 6 (D) 90 (126μm)

[0203] Fine lactose 1 (D) 90 (7.39μm)

[0204] Magnesium stearate (D) 90 :23μm)

[0205] Experimental Examples 26-29:

[0206] Inhalation powder can be prepared by the following method:

[0207] 1. Premix un-micronized glycopyrronium bromide and a portion of magnesium stearate on a Turbula three-dimensional motion mixer.

[0208] 2. The above premix is ​​pulverized in an air jet mill to obtain glycopyrronium bromide magnesium stearate intermediate.

[0209] 3. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 crude lactose (covering all mixing blades); approximately 1 / 2 of the remaining prescribed amount of magnesium stearate (excluding the co-micronized powder); approximately 1 / 2 fine lactose; approximately 1 / 2 micronized glycopyrronium bromide magnesium stearate intermediate; approximately 1 / 3 crude lactose; remaining micronized glycopyrronium bromide magnesium stearate intermediate; remaining fine lactose; remaining magnesium stearate; remaining crude lactose. After adding the materials, close the sealing cap.

[0210] 4. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0211] 5. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0212] 6. Pack the filled capsules in double aluminum packaging.

[0213] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 11.

[0214] Table 11 Results of product performance evaluation indicators in Test Examples 26-29

[0215]

[0216] The results of experiments 26-29 show that as the premixing ratio of glycopyrronium bromide and magnesium stearate approaches a certain level, the content uniformity and delivery stability of the product unexpectedly deteriorate. This indicates that a smaller premixing ratio of glycopyrronium bromide to magnesium stearate is less conducive to the uniform mixing of the active ingredients. Even when the premixing ratio of glycopyrronium bromide to magnesium stearate is 95:5, the content uniformity and delivery stability of the product are still unsatisfactory. Further process optimization is needed to improve product performance.

[0217] Experimental Examples 30-33:

[0218] Inhalation powder can be prepared by the following method:

[0219] 1. Using a Turbula three-dimensional motion mixer, a portion of the prescribed amount of crude lactose is premixed with the full amount of the prescribed amount of magnesium stearate to obtain a crude lactose complex.

[0220] 2. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 of the remaining prescribed amount of crude lactose (covering all mixing blades), excluding premix; approximately 1 / 2 of the crude lactose complex; approximately 1 / 2 of the fine lactose; approximately 1 / 2 of the micronized glycopyrronium bromide; approximately 1 / 3 of the remaining prescribed amount of crude lactose; the remaining micronized glycopyrronium bromide; the remaining fine lactose; the remaining crude lactose complex; the remaining crude lactose. After adding the materials, close the sealing cap.

[0221] 3. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0222] 4. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0223] 5. Pack the filled capsules in double aluminum packaging.

[0224] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 12.

[0225] Table 12 Results of product performance evaluation indicators for Test Examples 30-33

[0226]

[0227] The results of Experiments 30-33 show that when the premixing ratio of magnesium stearate and crude lactose is 1:5 to 1:20, the uniformity of the formulation content and the delivery stability are slightly improved compared with Experiments 26-29, but the FPF of the formulation is reduced.

[0228] Experimental Examples 34-37:

[0229] Inhalation powder can be prepared by the following method:

[0230] 1. Using a Turbula three-dimensional motion mixer, a portion of the prescribed amount of fine lactose is premixed with the entire prescribed amount of magnesium stearate to obtain a fine lactose complex.

[0231] 2. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 of the prescribed amount of crude lactose (covering all mixing blades); approximately 1 / 2 of the fine lactose complex; approximately 1 / 2 of the remaining prescribed amount of fine lactose (excluding premix); approximately 1 / 2 of the micronized glycopyrronium bromide; approximately 1 / 3 of the prescribed amount of crude lactose; the remaining micronized glycopyrronium bromide; the remaining fine lactose; the remaining fine lactose complex; the remaining crude lactose. After adding the materials, close the sealing cap.

[0232] 3. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0233] 4. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0234] 5. Pack the filled capsules in double aluminum packaging.

[0235] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 13.

[0236] Table 13 Results of product performance evaluation indicators in Test Examples 34-37

[0237]

[0238] The results of experiments 34-37 show that the products prepared using the premixing process of fine lactose and magnesium stearate exhibit improved content uniformity and delivery stability compared to previous experiments. Furthermore, the improvement in content uniformity and delivery stability becomes increasingly pronounced with increasing ratios of fine lactose and magnesium stearate. Therefore, the optimal premixing ratio of fine lactose and magnesium stearate is 20:1. However, unfortunately, no significant improvement in product feed effectiveness (FPF) was observed.

[0239] Experimental Examples 38-41:

[0240] Inhalation powder can be prepared by the following method:

[0241] 1. Using a Turbula three-dimensional motion mixer, a portion of the prescribed amount of fine lactose is premixed with the entire prescribed amount of magnesium stearate to obtain a fine lactose complex.

[0242] 2. Mix the fine lactose complex obtained in step 1 with glycopyrronium bromide to obtain a glycopyrronium bromide intermediate premix.

[0243] 3. Process the glycopyrronium bromide intermediate premix from step 2 into micronized powder to obtain micronized glycopyrronium bromide intermediate.

[0244] 4. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 of the prescribed amount of crude lactose (covering all mixing blades); approximately 1 / 2 of the micronized glycopyrronium bromide intermediate; approximately 1 / 2 of the remaining prescribed amount of fine lactose (excluding premix); approximately 1 / 3 of the prescribed amount of crude lactose; remaining fine lactose; remaining micronized glycopyrronium bromide intermediate; remaining crude lactose. After adding the materials, close the sealing cap.

[0245] 5. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0246] 6. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0247] 7. Pack the filled capsules in double aluminum packaging.

[0248] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 14.

[0249] Table 14 Results of product performance evaluation indicators for Test Examples 38-41

[0250]

[0251] The results of Experiments 38-41 show that the product obtained by using the process of preparing intermediates by co-micronizing glycopyrronium bromide, magnesium stearate and fine lactose, while ensuring that the content uniformity and delivery stability are basically the same as those of Experiments 34-37, has a slightly improved FPF. Preparing intermediates by co-micronizing the three substances is beneficial to improving the product FPF.

[0252] Experimental Examples 42-45:

[0253] Inhalation powder can be prepared by the following method:

[0254] 1. Using a Turbula three-dimensional motion mixer, a portion of the prescribed amount of fine lactose is premixed with the entire prescribed amount of magnesium stearate to obtain a fine lactose complex.

[0255] 2. Mix the fine lactose complex obtained in step 1 with glycopyrronium bromide to obtain a glycopyrronium bromide intermediate premix.

[0256] 3. Process the glycopyrronium bromide intermediate premix from step 2 into micronized powder to obtain micronized glycopyrronium bromide intermediate I.

[0257] 4. Using a Turbula three-dimensional motion mixer, mix glycopyrronium bromide intermediate I from step 3 with a certain mass of crude lactose to obtain glycopyrronium bromide intermediate II.

[0258] 5. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 of the prescribed amount of crude lactose (covering all agitator blades); approximately 1 / 2 of the micronized glycopyrronium bromide intermediate II; approximately 1 / 2 of the remaining prescribed amount of fine lactose (excluding premix); approximately 1 / 3 of the prescribed amount of crude lactose; remaining fine lactose; remaining micronized glycopyrronium bromide intermediate II; remaining crude lactose. After adding the materials, close the sealing cap.

[0259] 6. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0260] 7. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0261] 8. Pack the filled capsules in double aluminum packaging.

[0262] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 15.

[0263] Table 15 Results of product performance evaluation indicators for Test Examples 42-45

[0264]

[0265] The results of experiments 42-45 show that the product obtained using the process for preparing glycopyrronium bromide intermediate II exhibits improved content uniformity and delivery stability. Furthermore, the improvement in delivery stability becomes more pronounced with increasing ratio of glycopyrronium bromide intermediate I to crude lactose. Therefore, the preferred ratio of glycopyrronium bromide intermediate I to crude lactose is 1:5. In this experiment, the product FPF is comparable to that of the products prepared in experiments 38-41.

[0266] Experimental Examples 46-51:

[0267] Inhalation powder can be prepared by the following method:

[0268] 1. Using a Turbula three-dimensional motion mixer, a portion of the prescribed amount of fine lactose was premixed with a certain amount of magnesium stearate to obtain a fine lactose complex.

[0269] 2. Mix the fine lactose complex obtained in step 1 with glycopyrronium bromide to obtain a glycopyrronium bromide intermediate premix.

[0270] 3. Process the glycopyrronium bromide intermediate premix from step 2 into micronized powder to obtain micronized glycopyrronium bromide intermediate I.

[0271] 4. Using a Turbula three-dimensional motion mixer, mix glycopyrronium bromide intermediate I from step 3 with a certain mass of crude lactose to obtain glycopyrronium bromide intermediate II.

[0272] 5. Using a Turbula three-dimensional motion mixer, mix the remaining amount of magnesium stearate and crude lactose to obtain a magnesium stearate and crude lactose mixture.

[0273] 6. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 of the prescribed amount of magnesium stearate crude lactose mixture (covering all agitator blades); approximately 1 / 2 of the micronized glycopyrronium bromide intermediate II; approximately 1 / 2 of the remaining prescribed amount of fine lactose (excluding premix); approximately 1 / 3 of the prescribed amount of magnesium stearate crude lactose mixture; remaining fine lactose; remaining micronized glycopyrronium bromide intermediate II; remaining magnesium stearate crude lactose mixture. After adding the materials, close the sealing cap.

[0274] 7. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0275] 8. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0276] 9. Pack the filled capsules in double aluminum packaging.

[0277] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 16.

[0278] Table 16 Results of product performance evaluation indicators for Test Examples 46-51

[0279]

[0280] The results of experiments 46-49 show that the process of premixing a portion of fine lactose and a portion of the prescribed amount of magnesium stearate in step 1 unexpectedly and significantly improved the product's Faster Product Flow (FPF) while maintaining high content uniformity and delivery stability. Furthermore, the lower the amount of magnesium stearate used in step 1, the higher the product's FPF.

[0281] The specific APSD test results (calculated as glycopyrronium, the same below) are shown in Table 17.

[0282] Table 17 APSD detection results of test cases 46-51

[0283] Table 17 Test Case 46 Experimental Example 47 Test Case 48 Test Case 49 Test Case 50 Test Example 51 Device residue 1.14 1.05 1.18 1.13 1.19 1.17 Capsule residue 3.12 2.96 3.11 3.16 3.31 3.37 adapter 0.23 0.25 0.27 0.26 0.35 0.44 bend inlet 0.33 0.37 0.41 0.64 1.27 1.63 Pre-separator 1.11 1.39 1.45 1.87 2.53 3.02 Level 1 0.20 0.23 0.23 0.27 0.42 0.55 2 levels 1.16 1.24 1.32 1.45 1.83 1.97 3 levels 2.86 3.21 3.38 3.77 2.73 2.15 4 levels 2.00 2.09 2.17 2.31 1.85 1.34 5 levels 1.89 1.73 1.32 0.93 0.65 0.58 6 levels 1.45 1.33 1.09 0.85 0.56 0.43 7 levels 0.72 0.65 0.38 0.19 0.08 0.05 MOC 0.38 0.34 0.23 0.13 0.05 0.03 5~MOC 4.4 4.1 3.0 2.1 1.3 1.1 SUM(ug) 16.6 16.8 16.5 17.0 16.8 16.7 FPF 77% 75% 72% 65% 50% 40%

[0284] As can be seen from the APSD results of the products in Experiment Examples 46-51, as the amount of magnesium stearate used in step 1 increases, the FPF of the products gradually decreases, and the deposition amount in the 5-MOC layers gradually decreases. The main reason for the decrease in FPF is the decrease in the deposition amount in the 5-MOC layers.

[0285] Experimental Example 52: Animal Pharmacokinetic Study

[0286] Formulation selection: The self-developed formulations of test examples 46, 47, 48, 50 and 51 and the marketed formulation SeebriBreezhaler (specification: 50 μg glycopyrronium per capsule) were used.

[0287] Dosage frequency: Single dose.

[0288] Route of administration: Inhalation via mouth and nose

[0289] Experimental animals: SD rats

[0290] Grouping: A total of 48 male rats were divided into 6 groups of 8 rats each.

[0291] The dosing parameters are shown in Table 18.

[0292] Table 18 Dosing parameters for animal pharmacokinetic studies

[0293] Test items Dosage (μg / kg) <![CDATA[C max (pg / mL)]]> <![CDATA[T max (h)]]> <![CDATA[AUC 0~∞ (pg·hr / mL)]]> Marketed formulations (n=8) 250 1702.3±287.9 0.12±0.04 8854±772 Self-developed reagent (Experimental Example 46, n=8) 85 2285.6±329.2 0.10±0.01 12093±951 Self-developed reagent (Experimental Example 47, n=8) 85 1667.3±235.4 0.11±0.02 8312±707 Self-developed reagent (Experimental Example 48, n=8) 85 953±123.8 0.11±0.02 5143±463 Self-developed reagent (Experimental Example 50, n=8) 85 728.6±103.2 0.13±0.03 4013±331 Self-developed reagent (Experimental Example 51, n=8) 85 544.6±86.7 0.13±0.03 3167±268

[0294] The self-developed formulation in Example 46 had the highest FPF (77%); however, animal pharmacokinetic studies using this formulation showed that its C... max and AUC 0~∞ The levels were significantly higher than those of marketed formulations, suggesting that the self-developed formulation has a higher systemic exposure, which increases the risk of clinical side effects from inhaled drugs. (Example 47: Self-developed formulation C) max and AUC 0~∞ Compared with marketed formulation C max and AUC 0~∞ Equivalent; Self-developed reagent C produced in test examples 48, 50 and 51 max The concentration was significantly lower than that of the marketed formulation. Based on the in vitro APSD data from Test Cases 46-51, it is inferred that the product's FPF, particularly the deposition of the 5-MOC layers in the APSD, affects the product's C. max By adjusting the amount of magnesium stearate in step 1, the product's FPF and 5~MOC deposition levels can be effectively regulated, thereby effectively regulating the product's pharmacokinetic performance in animals.

[0295] As shown in Experiments 46-52, when the FPF in the aerodynamic particle size distribution (APSD) of the product is 77% and the deposition amount of the 5-MOC strata is 4.4 μg, the pharmacokinetic parameter C of the self-developed agent in animals is... max The significantly higher FPF compared to marketed formulations suggests that self-developed formulations have a higher systemic exposure. Higher systemic exposure increases the risk of clinical side effects from inhaled drugs. Therefore, the FPF of self-developed formulations should not exceed 77%, and correspondingly, the 5-MoC deposition should be less than 4.4 μg. However, excessively low FPF and 5-MoC deposition may also lead to insufficient efficacy. Therefore, to ensure product efficacy, animal tissue distribution studies are needed to guide the determination of the product's FPF and 5-MoC deposition range.

[0296] Experimental Example 53: Animal Tissue Distribution Experiment

[0297] Formulation selection: The self-developed formulations of test examples 47, 49, 50 and 51 and the marketed formulation Seebri Breezhaler (specification: 50 μg glycopyrronium per capsule) were used.

[0298] Dosage frequency: Single dose.

[0299] Route of administration: Inhalation via mouth and nose

[0300] Experimental animals: SD rats

[0301] Grouping: A total of 72 SD rats were divided into two groups: a marketed formulation group (250 μg / kg dose) and a self-developed formulation group (85 μg / kg dose), with 36 rats in each group. Drug concentrations were collected in plasma, bronchoalveolar lavage fluid, lung tissue, nasopharynx (including turbinates), larynx (including epiglottis), main trachea and bronchi, and heart, liver, and kidneys at three time points after drug administration. The results are shown in Tables 19-21.

[0302] Table 19 Distribution of glycopyrronium bromide in key tissues of rats at different time points after inhalation of marketed and self-developed formulations (t=0.5h)

[0303] Tissue distribution (ng / g) Marketed formulations Experimental Example 47: Self-developed reagent Experimental Example 49: Self-developed reagent Experimental Example 50: Self-developed reagent Experimental Example 51: Self-developed reagent plasma 25.4±6.8 21.6±5.3 15.1±4.1 8.7±1.9 6.3±1.6 bronchoalveolar lavage fluid 98.3±24.6 97.9±25.7 85.3±21.1 66.1±15.5 45.7±9.9 lung tissue 119.2±34.8 106.4±29.6 97.4±26.3 72.5±17.8 58.2±12.8 Nasopharynx (including nasal turbinates) 153.5±41.7 43.7±10.2 53.9±13.4 79.8±20.1 98.3±24.3 The throat (including the epiglottis) 172.8±50.3 55.9±13.9 67.2±16.0 90.1±22.0 115.4±35.8 Main trachea and bronchi 32.3±9.4 93.1±22.8 113±32.8 67.3±17.2 29.8±8.2 heart 6.7±1.9 5.2±1.4 1.3±0.3 1.1±0.3 0.9±0.2 liver 1.9±0.4 1.2±0.3 0.6±0.2 0.4±0.1 0.3±0.1 kidney 1.2±0.3 0.9±0.3 0.5±0.2 0.4±0.1 0.2±0.0

[0304] Table 20 Distribution of glycopyrronium bromide in key tissues of rats at different time points after inhalation of marketed and self-developed formulations (t=2h)

[0305] Tissue distribution (ng / g) Marketed formulations Experimental Example 47: Self-developed reagent Experimental Example 49: Self-developed reagent Experimental Example 50: Self-developed reagent Experimental Example 51: Self-developed reagent plasma 4.3±1.2 3.7±0.9 2.9±0.7 1.4±0.3 0.9±0.2 bronchoalveolar lavage fluid 49.2±10.7 42.8±8.7 31.7±9.4 23.5±5.7 18.7±4.7 lung tissue 66.7±16.3 54.6±11.9 38.2±10.9 26.4±6.0 19.5±5.2 Nasopharynx (including nasal turbinates) 78.4±19.8 27.6±6.8 33.3±10.2 46.0±9.9 57.3±12.3 The throat (including the epiglottis) 89.5±23.4 35.3±10.3 47.6±11.3 58.1±12.3 69.3±16.7 Main trachea and bronchi 28.9±7.9 64.3±16.9 72.1±18.3 38.4±11.2 14.8±3.6 heart 13.1±3.0 11.5±3.2 3.0±0.7 2.3±0.6 1.8±0.4 liver 5.8±1.5 4.9±1.3 1.7±0.4 1.4±0.3 1.0±0.1 kidney 4.9±1.4 3.4±0.8 1.5±0.4 1.3±0.3 0.8±0.1

[0306] Table 21 Distribution of glycopyrronium bromide in key tissues of rats at different time points after inhalation of marketed and self-developed formulations (t=4h)

[0307] Tissue distribution (ng / g) Marketed formulations Experimental Example 47: Self-developed reagent Experimental Example 49: Self-developed reagent Experimental Example 50: Self-developed reagent Experimental Example 51: Self-developed reagent plasma 1.6±0.5 1.3±0.3 0.8±0.2 0.7±0.2 0.5±0.1 bronchoalveolar lavage fluid 20.3±5.3 18.4±4.4 13.4±4.1 9.5±2.7 7.3±2.3 lung tissue 27.8±6.1 20.5±5.7 15.7±4.7 11.3±3.4 8.7±2.4 Nasopharynx (including nasal turbinates) 30.4±9.4 13.2±3.8 16.0±4.9 20.4±5.1 28.6±8.7 The throat (including the epiglottis) 41.3±10.8 16.9±4.5 21.0±5.0 29.1±9.3 35.5±10.2 Main trachea and bronchi 11.6±3.3 22.5±5.9 29.8±5.8 23.8±5.9 10.7±2.9 heart 4.4±1.1 3.1±0.8 1.3±0.4 1.1±0.3 0.9±0.2 liver 2.2±0.3 1.4±0.4 0.7±0.2 0.6±0.2 0.5±0.1 kidney 1.8±0.8 1.0±0.2 0.6±0.2 0.5±0.1 0.4±0.1

[0308] The tissue distribution test data show that:

[0309] After rats inhaled the marketed formulation for 0.5 hours, the drug was mainly detected in the larynx (including the epiglottis), nasopharynx (including the turbinates), lung tissue, bronchoalveolar lavage fluid, main trachea and bronchi, and plasma. The drug concentration from highest to lowest was: larynx (including the epiglottis) > nasopharynx (including the turbinates) > lung tissue > bronchoalveolar lavage fluid > main trachea and bronchi > plasma > other organs. After rats inhaled the marketed formulation for 2 hours, the drug was mainly detected in the nasopharynx, larynx, lung tissue, and bronchoalveolar lavage fluid. At this time, the drug concentration in the heart, liver, and kidneys increased significantly. After rats inhaled the marketed formulation for 4 hours, in addition to the high concentrations in the nasopharynx, larynx, lung tissue, and bronchoalveolar lavage fluid, the drug concentrations in the heart, liver, and kidneys were still considerable compared to 2 hours after inhalation.

[0310] The main difference between rats inhaling the self-developed formulation for 0.5 hours and the marketed formulation for 0.5 hours was that the concentration of the self-developed formulation in the nasopharynx and larynx was significantly lower than that of the marketed formulation, while the concentration in the main trachea and bronchi was significantly higher (except for the self-developed formulation in Experiment 51). Two hours after inhalation, the drug was mainly detected in the main trachea and bronchi, bronchoalveolar lavage fluid, lung tissue, nasopharynx, and larynx. Except for the self-developed formulation in Experiment 51, the concentration of the self-developed formulation in the main trachea and bronchi was still significantly higher than that of the marketed formulation after 2 hours of inhalation. At this time, the drug concentration in the heart, liver, and kidneys increased significantly, but the concentration was still significantly lower than that of the marketed formulation. Four hours after inhalation, the most significant difference between the self-developed formulation and the marketed formulation was that the concentration of the self-developed formulation in the heart, liver, and kidneys was significantly lower than that of the marketed formulation, and the self-developed formulation showed an even lower concentration than at 2 hours of inhalation.

[0311] It is noteworthy that when rats inhaled self-prepared formulations with different FPFs (or 5-MoC deposition), the drug distribution in various tissues varied. For example, after 0.5 hours of inhalation of the self-prepared formulation: when the FPF of the self-prepared formulation decreased from 75% (self-prepared formulation in Experiment 47) to 40% (self-prepared formulation in Experiment 51), the drug concentrations in plasma, lung tissue, and bronchoalveolar lavage fluid gradually decreased, while the concentrations in the nasopharynx and larynx gradually increased. The concentrations in the main trachea and bronchi showed a trend of first increasing and then decreasing. The highest concentration was observed in the main trachea in the self-prepared formulation of Experiment 49 (65% FPF). And the concentration of the drug in the bronchus. In the self-developed formulation of test example 51 (FPF of 40%), the concentration of the drug in the main trachea and bronchi was lower than that of the marketed formulation, suggesting that the efficacy of the product may be lower than that of the marketed formulation. That is, when the FPF in the aerodynamic particle size distribution (APSD) of the product is 40% and the 5-MoC layer deposition amount is 1.1 μg, the concentration of the self-developed formulation in the effective site (main trachea and bronchi) is lower than that of the marketed formulation, suggesting that the efficacy of the self-developed formulation may be worse than that of the marketed formulation. Therefore, the FPF of the self-developed formulation should not be lower than 40%, and correspondingly, the 5-MoC deposition amount should be higher than 1.1 μg.

[0312] in conclusion:

[0313] Glycerone bromide is a quaternary ammonium anticholinergic drug that specifically binds to and inhibits M3 acetylcholine receptors distributed in bronchial smooth muscle, thereby dilating the airways. For glycopyrronium bromide, the main sites of receptor distribution are the main trachea and bronchial smooth muscle; therefore, drug deposition in these areas is considered beneficial. High concentrations of the drug in plasma, lung tissue, and bronchoalveolar lavage fluid result in high systemic exposure, while high concentrations in the larynx and nasopharynx may indicate increased respiratory irritation. In summary, tissue distribution data indicate that:

[0314] 1. The self-developed formulation produces higher effective site drug concentrations (main trachea and bronchi) than the marketed formulation. Specifically, within 0.5 to 4 hours after administration, the drug concentrations of the self-developed formulation (except for the self-developed formulation in Example 51) in the main trachea and bronchi are significantly higher than those of the marketed formulation, indicating that the self-developed formulation has superior efficacy. 2. Within 0.5 to 4 hours after administration, the drug concentrations of the self-developed formulation in the larynx, nasopharynx, heart, liver, and kidneys are significantly lower than those of the marketed formulation, indicating that the self-developed formulation has lower toxicity (such as respiratory irritation) and higher safety profile than the marketed formulation. 3. To ensure that the drug concentrations of the self-developed formulation in the main trachea and bronchi are higher than those of the marketed formulation, the FPF of the self-developed formulation is further preferably 50%–75%, and the deposition amount at the 5–MOC level is further preferably 1.3 μg–4.1 μg.

[0315] Based on the self-developed formulation preparation process, the optimal amount of magnesium stearate in step 1 is 1 / 8 to 3 / 5 of the formulation amount. At this point, the product's FPF ranges from 50% to 75%, and the deposition amount at the 5-MOC level is 1.3 μg to 4.1 μg. While ensuring efficacy, the product's safety is significantly improved.

[0316] Experimental Examples 54-58: Drug Dosage Selection

[0317] Inhalation powder can be prepared by the following method:

[0318] 1. Using a Turbula three-dimensional motion mixer, a portion of the fine lactose was premixed with 3 / 5 of the prescribed amount of magnesium stearate to obtain a fine lactose complex.

[0319] 2. Mix the fine lactose complex obtained in step 1 with glycopyrronium bromide to obtain a glycopyrronium bromide intermediate premix.

[0320] 3. Process the glycopyrronium bromide intermediate premix from step 2 into micronized powder to obtain micronized glycopyrronium bromide intermediate I.

[0321] 4. Using a Turbula three-dimensional motion mixer, mix glycopyrronium bromide intermediate I from step 3 with a certain mass of crude lactose to obtain glycopyrronium bromide intermediate II.

[0322] 5. Using a Turbula three-dimensional motion mixer, mix the remaining amount of magnesium stearate and crude lactose to obtain a magnesium stearate and crude lactose mixture.

[0323] 6. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 of the prescribed amount of magnesium stearate crude lactose mixture (covering all agitator blades); approximately 1 / 2 of the micronized glycopyrronium bromide intermediate II; approximately 1 / 2 of the remaining prescribed amount of fine lactose (excluding premix); approximately 1 / 3 of the prescribed amount of magnesium stearate crude lactose mixture; remaining fine lactose; remaining micronized glycopyrronium bromide intermediate II; remaining magnesium stearate crude lactose mixture. After adding the materials, close the sealing cap.

[0324] 7. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0325] 8. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0326] 9. Pack the filled capsules in double aluminum packaging.

[0327] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 22.

[0328] Table 22 Results of product performance evaluation indicators for Test Examples 54-58

[0329]

[0330] When the concentration of glycopyrronium in the formulation is 0.05%w / w to 0.34%w / w, the product prepared using the above process has good content uniformity and aerodynamic characteristics.

[0331] Experimental Example 59: Animal Pharmacokinetic Study

[0332] Formulation selection: The self-developed formulation produced in Experiment Examples 54-58 and the marketed formulation Seebri Breezhaler (specification: 50 μg glycopyrronium per capsule) were used.

[0333] Dosage frequency: Single dose.

[0334] Route of administration: Inhalation via mouth and nose

[0335] Experimental animals: SD rats

[0336] Grouping: A total of 108 SD rats were divided into 6 groups of 18 rats each. The groups were: a marketed formulation group (250 μg / kg dose) and self-developed formulations (samples 54-58) at doses of 25 μg / kg, 65 μg / kg, 85 μg / kg, 100 μg / kg, and 170 μg / kg respectively. Drug concentrations were collected at 0.5 h and 4 h after administration in the nasopharynx (including turbinates), larynx (including epiglottis), main trachea and bronchi, and the heart, liver, and kidneys. The results are shown in Table 23.

[0337] Table 23 Distribution of glycopyrronium bromide in important tissues in rats at different time points after inhalation of the marketed formulation and the self-developed formulation.

[0338]

[0339] Comparison of test examples 54 (5.0 μg glycopyrronium per capsule), 55 (13.0 μg glycopyrronium per capsule), 56 (17.0 μg glycopyrronium per capsule), 57 (20.0 μg glycopyrronium per capsule), and 58 (34.0 μg glycopyrronium per capsule) with the marketed formulation revealed that when each capsule contained 5.0 μg, 13.0 μg, 17.0 μg, and 20 μg glycopyrronium, the concentration of the self-developed formulation at the effective sites (main trachea and bronchi) was higher than that of the marketed formulation, while the concentrations at sites potentially causing side effects (nasopharynx, larynx, heart, liver, and kidneys) were significantly lower. When each capsule contained 34.0 μg glycopyrronium, although the concentration of the self-developed formulation at the effective sites (main trachea and bronchi) was significantly higher than that of the marketed formulation, its concentrations at the nasopharynx and larynx were also significantly higher, suggesting a higher risk of respiratory irritation and other side effects compared to the marketed formulation.

[0340] Conclusion: Glycerin at a concentration not exceeding 20 μg per tablet can still achieve or exceed the efficacy of marketed formulations and significantly reduce the occurrence of side effects.

[0341] Experimental Examples 60-61: Stability Study of the Formulation

[0342] Stability was investigated for test examples 54 and 57. The stability test conditions are shown in Table 24, and the results are shown in Table 25.

[0343] Table 24 Stability test conditions for test examples 54 and 57

[0344] Examination conditions specific conditions accelerate Temperature: 40℃±2℃ Relative Humidity: 75%±5%

[0345] Table 25 Stability test results for Test Examples 54 and 57

[0346]

[0347] The experimental results show that when the concentration of glycopyrronium in the formulation is 0.05% w / w and 0.20% w / w (equivalent to 5.0 μg and 20.0 μg of glycopyrronium per capsule), the product prepared by the process of this invention has good stability.

[0348] Experimental Examples 62-66: Screening of Vectors

[0349] The characteristics of self-prepared reagents using different carriers were examined, and the preparation process is as follows:

[0350] Inhalation powder can be prepared by the following method:

[0351] 1. Using a Turbula three-dimensional motion mixer, a portion of the carrier (fine) was premixed with 1 / 2 of the prescribed amount of magnesium stearate to obtain the carrier complex.

[0352] 2. Mix the carrier complex obtained in step 1 with glycopyrronium bromide to obtain a glycopyrronium bromide intermediate premix.

[0353] 3. Process the glycopyrronium bromide intermediate premix from step 2 into micronized powder to obtain micronized glycopyrronium bromide intermediate I.

[0354] 4. Using a Turbula three-dimensional motion mixer, mix the glycopyrronium bromide intermediate I from step 3 with a certain mass of carrier (crude) to obtain glycopyrronium bromide intermediate II.

[0355] 5. Using a Turbula three-dimensional motion mixer, mix the remaining amount of magnesium stearate and the remaining amount of carrier (crude) to obtain a magnesium stearate-carrier mixture.

[0356] 6. Use a GEA high-speed mixing unit to mix the materials in the mixer in the following order, spreading them alternately: approximately 1 / 3 of the prescribed amount of magnesium stearate-carrier mixture (covering all agitator blades); approximately 1 / 2 of the micronized glycopyrronium bromide intermediate II; approximately 1 / 2 of the remaining prescribed amount of carrier (fine), excluding premix; approximately 1 / 3 of the prescribed amount of magnesium stearate-carrier mixture; remaining carrier (fine); remaining micronized glycopyrronium bromide intermediate II; remaining magnesium stearate-carrier mixture. After adding the materials, close the sealing cap.

[0357] 7. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0358] 8. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0359] 9. Pack the filled capsules in double aluminum packaging.

[0360] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 26.

[0361] Table 26 Results of product performance evaluation indicators for Test Examples 62-66

[0362]

[0363] Experimental conclusion: When dextran, mannitol, xylitol, phosphatidylcholine, and cholesterol are used as carriers, the formulation content meets the requirements, and the FPF and 5~MOC are comparable to those when lactose is used as a carrier.

[0364] Experimental Examples 67-71: Screening of Carrier Particle Size

[0365] The effect of carrier particle size on key quality attributes of the formulation was investigated. The same process as in Experiments 62-66 was used.

[0366] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 27 (lactose was selected as the carrier in this experimental example).

[0367] Table 27 Results of product performance evaluation indicators for Test Examples 67-71

[0368]

[0369] Conclusion: When the particle size range of crude lactose (large particle size carrier) is within D... 10 The diameter is 4~10μm, D 50 30~60μm, D 90 The particle size ranges from 80 to 150 μm; fine lactose (small particle size carrier) has a particle size range of D. 10 The range is 0.4~1.2μm, D 50 The range is 1.5~4.7μm, D 90 When the thickness is 5.0~20.0 μm, the key quality attributes of the formulation are comparable to those of the formulation in the aforementioned test example 49.

[0370] Experimental Examples 72-75: Screening of Small Particle Size Carrier Content

[0371] Under the process conditions specified in this patent application, the effect of small-particle-size carrier content on key quality attributes of the formulation was investigated. The process used was the same as that used in Experiments 62-66.

[0372] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 28 (lactose was selected as the carrier in this experimental example).

[0373] Table 28 Results of product performance evaluation indicators for Test Examples 72-75

[0374]

[0375] Conclusion: When the content of fine lactose (small particle size carrier) is in the range of 2.0% w / w to 6.0% w / w, the key quality attributes of the formulation are comparable to those of the formulation in the aforementioned Example 49. When the content of fine lactose (small particle size carrier) is 8% w / w, the product content uniformity and aerodynamic properties show a deteriorating trend.

[0376] Experimental Examples 76-79: Screening of Dispersing Agents

[0377] The effect of the type of dispersant on the key properties of the formulation was investigated. The process used was the same as that used in Experiments 62-66.

[0378] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 29.

[0379] Table 29 Results of product performance evaluation indicators for Test Examples 76-79

[0380]

[0381] Experimental conclusion: When magnesium stearate, sodium stearate, calcium stearate and colloidal silica are used as dispersants, the properties of the formulation are comparable to those when magnesium stearate is used as the dispersant.

[0382] Experimental Examples 80-84: Screening of Dispersing Agent Particle Size

[0383] The effect of dispersant particle size on key properties of the formulation was investigated. The process used was the same as that used in Experiments 62-66.

[0384] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are listed in Table 30 (magnesium stearate was selected as the dispersant in this test).

[0385] Table 30 Results of product performance evaluation indicators for Test Examples 80-84

[0386]

[0387] Conclusion: When the particle size range of magnesium stearate (dispersant) is within D... 10 The range is 2.2~4.2μm, D 50 The range is 7.2~11.5μm, D 90 When the size is 16~30μm, the key quality attributes of the formulation are comparable to those of the formulation in the aforementioned test example 49.

[0388] Experimental Examples 85-88: Screening of Dispersant Content

[0389] Under the process conditions specified in this patent application, the effect of the dispersant content on the key quality attributes of the formulation was investigated. The process used was the same as that used in Experimental Examples 62-66.

[0390] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 31 (magnesium stearate was selected as the dispersant in this experimental example).

[0391] Table 31 Results of product performance evaluation indicators for Test Examples 85-88

[0392]

[0393] Conclusion: When the magnesium stearate (dispersant) content is in the range of 0.1% w / w to 0.5% w / w, the key quality attributes of the formulation are comparable to those of the formulation in Example 49 above. When the magnesium stearate (dispersant) content is 0.7% w / w, the uniformity of product content and aerodynamic properties show a deteriorating trend.

[0394] Experimental Examples 89-96: Screening of Aliphatic Polyesters

[0395] The effect of adding aliphatic polyesters to the formulation on the key properties of the formulation was investigated. The process used was the same as that used in Experiments 62-66.

[0396] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 32.

[0397] Table 32 Results of product performance evaluation indicators for test examples 89-96

[0398]

[0399] Conclusions: When the polyglycolic acid content is in the range of 0.08% w / w to 0.12% w / w, the critical quality attributes of the formulation are comparable to those of the formulation in Test Example 49 above. When the content exceeds 0.12%, the FPF decreases. When the polycaprolactone content is in the range of 0.08% w / w to 0.15% w / w, the critical quality attributes of the formulation are comparable to those of the formulation in Test Example 49 above.

[0400] Experimental Examples 97-102: Screening of Aliphatic Polyester Particle Size

[0401] The effect of aliphatic polyesters on the key particle size properties of the formulation was investigated. The process used was the same as that used in Experiments 62-66.

[0402] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 33.

[0403] Table 33 Results of product performance evaluation indicators for Test Examples 97-102

[0404]

[0405] Experimental conclusion:

[0406] When the particle size distribution range of polyglycolic acid is: D 10 The diameter is 0.5~0.7μm, D 50 The diameter is 1.2~2.0μm, D 90The particle size distribution range of polycaprolactone is 3.0~5.0 μm. 10 The thickness is 1.0~1.5μm, D 50 The diameter is 2.5~3.5μm, D 90 When the thickness is 5.0~7.0 μm, the critical quality attributes of the formulation are comparable to those of the formulation in the aforementioned test example 49.

[0407] Experimental Examples 103-109: Investigation of Process Parameters

[0408] The effects of process parameters on various indicators of the formulation were investigated. The preparation process is as follows:

[0409] Inhalation powder can be prepared by the following method:

[0410] 1. Using a Turbula three-dimensional motion mixer, a portion of the carrier (fine) was premixed with half the amount of magnesium stearate in the prescription to obtain the carrier-complex.

[0411] 2. Mix the carrier complex obtained in step 1 with glycopyrronium bromide to obtain a glycopyrronium bromide intermediate premix.

[0412] 3. Process the glycopyrronium bromide intermediate premix from step 2 into micronized powder (see the table below for specific parameters) to obtain micronized glycopyrronium bromide intermediate I.

[0413] 4. Using a Turbula three-dimensional motion mixer, mix the glycopyrronium bromide intermediate I from step 3 with a certain mass of carrier (crude) (mixing parameters are shown in the table below) to obtain glycopyrronium bromide intermediate II.

[0414] 5. Using a Turbula three-dimensional motion mixer, mix the remaining amount of magnesium stearate and the remaining amount of carrier (crude) to obtain a magnesium stearate-carrier mixture.

[0415] 6. Use a GEA high-speed mixing unit to mix the materials in the mixer in the following order, spreading them alternately: approximately 1 / 3 of the prescribed amount of magnesium stearate-carrier mixture (covering all agitator blades); approximately 1 / 2 of the micronized glycopyrronium bromide intermediate II; approximately 1 / 2 of the remaining prescribed amount of carrier (fine), excluding premix; approximately 1 / 3 of the prescribed amount of magnesium stearate-carrier mixture; remaining carrier (fine); remaining micronized glycopyrronium bromide intermediate II; remaining magnesium stearate-carrier mixture. After adding the materials, close the sealing cap.

[0416] 7. Set the mixing linear velocity and mixing time, as shown in the table below.

[0417] 8. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0418] 9. Pack the filled capsules in double aluminum packaging.

[0419] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 34.

[0420] Table 34 Results of product performance evaluation indicators for Test Examples 103-109

[0421]

[0422] The experimental conclusions are as follows: In process step 3, when the feed pressure is 3~9 bar, the pulverizing pressure is 2~8 bar, and the feed speed is 5~30 rpm, there is basically no effect on the various indicators of the formulation. In process step (4), when the mixing speed is 30~90 Hz and the mixing time is 10~60 min, there is basically no effect on the various indicators of the formulation. In process step (5), when the mixing linear velocity is 3~12 m / s and the mixing time is 3~9 min, there is basically no effect on the various indicators of the formulation.

[0423] Experimental Examples 110-113: Preparation of Compound Inhalation Formulations

[0424] Inhalation powder containing formoterol fumarate and glycopyrronium bromide was prepared by the following method:

[0425] 1. Using a Turbula three-dimensional motion mixer, premix a portion of the prescribed amount of fine lactose with half the prescribed amount of magnesium stearate to obtain a fine lactose complex.

[0426] 2. Mix the fine lactose complex obtained in step 1 with glycopyrronium bromide and formoterol fumarate to obtain a glycopyrronium bromide formoterol intermediate premix.

[0427] 3. Process the glycopyrronium bromide formoterol intermediate premix from step 2 into micronized powder to obtain micronized glycopyrronium bromide formoterol intermediate I.

[0428] 4. Using a Turbula three-dimensional motion mixer, mix the glycopyrronium bromide formoterol intermediate I from step 3 with a certain mass of crude lactose to obtain glycopyrronium bromide formoterol intermediate II.

[0429] 5. Using a Turbula three-dimensional motion mixer, mix the remaining amount of magnesium stearate and crude lactose to obtain a magnesium stearate and crude lactose mixture.

[0430] 6. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 of the prescribed amount of magnesium stearate crude lactose mixture (covering all agitator blades); approximately 1 / 2 of the micronized glycopyrronium bromide formoterol intermediate II; approximately 1 / 2 of the remaining prescribed amount of fine lactose (excluding premix); approximately 1 / 3 of the prescribed amount of magnesium stearate crude lactose mixture; remaining fine lactose; remaining micronized glycopyrronium bromide formoterol intermediate II; remaining magnesium stearate crude lactose mixture. After adding the materials, close the sealing cap.

[0431] 7. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0432] 8. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0433] 9. Pack the filled capsules in double aluminum packaging.

[0434] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 35 below.

[0435] Table 35 Results of product performance evaluation indicators for Test Examples 110-113

[0436]

[0437] Conclusion: In glycopyrronium bromide-formoterol compound preparations, when the mass percentage of formoterol is 0.06% w / w to 0.15%, the uniformity of the content of the two active ingredients in the preparation is less than 2%, and the FPF is in the range of 50% to 75%.

[0438] Experimental Examples 114-117: Preparation of Three-Part Inhalation Formulations

[0439] Inhalation powder containing formoterol fumarate, glycopyrronium bromide, and budesonide was prepared by the following method:

[0440] 1. Using a Turbula three-dimensional motion mixer, premix a portion of the prescribed amount of fine lactose with half the prescribed amount of magnesium stearate to obtain a fine lactose complex.

[0441] 2. The lactose complex obtained in step 1 is mixed with glycopyrronium bromide, formoterol fumarate and budesonide to obtain the budesonide-glucose intermediate premix.

[0442] 3. Process the budesonite intermediate premix from step 2 into micronized powder to obtain micronized budesonite intermediate I.

[0443] 4. Using a Turbula three-dimensional motion mixer, mix the Budegfor intermediate I from step 3 with a certain mass of crude lactose to obtain Budegfor intermediate II.

[0444] 5. Using a Turbula three-dimensional motion mixer, mix the remaining amount of magnesium stearate and crude lactose to obtain a magnesium stearate and crude lactose mixture.

[0445] 6. Use a GEA high-speed mixing unit to mix the materials in the following order, spreading them alternately in the mixer: approximately 1 / 3 of the prescribed amount of magnesium stearate crude lactose mixture (covering all agitator blades); approximately 1 / 2 of micronized Budigfe intermediate II; approximately 1 / 2 of the remaining prescribed amount of fine lactose (excluding premix); approximately 1 / 3 of the prescribed amount of magnesium stearate crude lactose mixture; remaining fine lactose; remaining micronized Budigfe intermediate II; remaining magnesium stearate crude lactose mixture. After adding the materials, close the sealing cap.

[0446] 7. Set the mixing linear velocity to 9.0 m / s and mix for 6 minutes.

[0447] 8. Test the uniformity of the total mixture obtained above and fill the capsules with a filling amount of 12.5 mg.

[0448] 9. Pack the filled capsules in double aluminum packaging.

[0449] The performance of the above products was evaluated using a dry powder inhaler. Evaluation indicators included product content uniformity, delivery stability, and FPF. Specific test results are shown in Table 36 below.

[0450] Table 36 Results of product performance evaluation indicators in Test Examples 114-117

[0451]

[0452] Conclusion: In budesonide-glycopyrronium bromide-formoterol combination preparations, when the mass percentage of budesonide is 1.0% w / w to 5.0% w / w, the uniformity of the content of the three active ingredients in the preparation is less than 2%, and the FPF is in the range of 50% to 75%.

[0453] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A capsule-type inhaled powder, characterized in that, The powder atomizer is composed of an active ingredient, a dispersant, and a carrier. The active ingredient is glycopyrronium bromide, and the content of glycopyrronium bromide in each capsule is 11.0~20.0 μg, calculated as glycopyrronium. The aerodynamic characteristics show an FPF of 50.0~75.0%. In APSD, the deposition amount of 5~MOC levels ranged from 1.3 μg to 4.1 μg; the content uniformity was RSD ≤ 5%. The preparation method of the capsule-type inhaled powder includes the following steps: The active ingredient, dispersant, and carrier are provided according to the prescription, and the carrier is divided into large-particle-size carrier and small-particle-size carrier; A carrier complex is obtained by mixing a portion of the dispersing agent with a portion of the small-particle-size carrier. The carrier complex is mixed with the active ingredient and then micronized to obtain active ingredient intermediate I; Active ingredient intermediate I is mixed evenly with a portion of large-particle-size carrier to obtain active ingredient intermediate II, and active ingredient intermediate II is then mixed evenly with the remaining formulation ingredients. A portion of the dispersing agent and a portion of the small-particle-size carrier are mixed at a weight ratio of 1:5~20; The particle size distribution range of large-particle-size carriers is: D 10 The diameter is 4~10μm, D 50 30~60μm, D 90 The thickness is 80~150μm; The particle size distribution range of small-diameter carriers is: D 10 The range is 0.4~1.2μm, D 50 The range is 1.5~4.7μm, D 90 The range is 5.0~20.0μm; The particle size distribution range of the dispersing agent is: D 10 The range is 2.2~4.2μm, D 50 The range is 7.2~11.5μm, D 90 The thickness is 16~30μm; The content of small-particle-size carriers is 2.0~6.0% of the total weight of the powder aerosol formulation; The carrier is one or more of lactose, dextran, mannitol, xylitol, phosphatidylcholine, and cholesterol; The dispersing agent is one or more of sodium stearate, magnesium stearate, calcium stearate, and colloidal silica; The content of the dispersing agent is 0.1 to 0.5% of the total weight of the powder aerosol formulation.

2. The capsule-type inhaled powder as described in claim 1, characterized in that... The content of glycopyrronium bromide, calculated as glycopyrronium, in each capsule is 13.0~18.0 μg.

3. The capsule-type inhaled powder as described in claim 1, characterized in that, The FPF in the aerodynamic characteristics is 55.0~72.0%.

4. The capsule-type inhaled powder as described in claim 3, characterized in that, The FPF in the aerodynamic characteristics is 59.0~69.0%.

5. The capsule-type inhaled powder as described in claim 4, characterized in that, In APSD, the deposition amount of 5~MOC layers ranges from 2.0 μg to 3.5 μg.

6. The capsule-type inhaled powder as described in claim 5, characterized in that, In APSD, the deposition amount of 5~MOC layers is 2.0 μg~3.0 μg.

7. The capsule-type inhaled powder as described in claim 6, characterized in that, The content uniformity is RSD≤3%.

8. The capsule-type inhaled powder as described in claim 7, characterized in that, The content uniformity is RSD≤2%.

9. The capsule-type inhaled powder as described in claim 1, characterized in that, The content of glycopyrronium bromide is 0.05~0.20% of the total weight of the powder inhaler formulation.

10. The capsule-type inhaled powder as described in claim 1, characterized in that, It further includes polyglycolic acid or polycaprolactone, wherein the content of polyglycolic acid is 0.08 to 0.12% of the total weight of the powder formulation; and the content of polycaprolactone is 0.08 to 0.15% of the total weight of the powder formulation.

11. The capsule-type inhaled powder as described in claim 10, characterized in that, The particle size distribution range of polyglycolic acid is: D 10 The diameter is 0.5~0.7μm, D 50 The diameter is 1.2~2.0μm, D 90 The particle size distribution range of polycaprolactone is 3.0~5.0 μm; D 10 The thickness is 1.0~1.5μm, D 50 The diameter is 2.5~3.5μm, D 90 The thickness is 5.0~7.0μm.

12. The capsule-type inhaled powder as described in claim 1, characterized in that, The active ingredients also include one or more of formoterol, indacaterol, salmeterol, and vilanterol, which account for 0.06% to 0.15% of the total mass of the formulation.

13. The capsule-type inhaled powder as described in claim 12, characterized in that, The active ingredients also include at least one or more of budesonide, ccyclosone, and triamcinolone, which account for 1.0% to 5.0% of the mass of the formulation.

14. A method for preparing the capsule-type inhaled powder according to claim 1, characterized in that it includes: The process is as follows: The active ingredient, dispersant, and carrier are provided according to the prescription, and the carrier is divided into large-particle-size carrier and small-particle-size carrier; A carrier complex is obtained by mixing a portion of the dispersing agent with a portion of the small-particle-size carrier. The carrier complex is mixed with the active ingredient and then micronized to obtain active ingredient intermediate I; Active ingredient intermediate I is mixed evenly with a portion of large-particle-size carrier to obtain active ingredient intermediate II, and active ingredient intermediate II is then mixed evenly with the remaining formulation ingredients. A portion of the dispersing agent and a portion of the small-particle-size carrier are mixed at a weight ratio of 1:5~20; The particle size distribution range of large-particle-size carriers is: D 10 The diameter is 4~10μm, D 50 30~60μm, D 90 The thickness is 80~150μm; The particle size distribution range of small-diameter carriers is: D 10 The range is 0.4~1.2μm, D 50 The range is 1.5~4.7μm, D 90 The range is 5.0~20.0μm; The particle size distribution range of the dispersing agent is: D 10 The range is 2.2~4.2μm, D 50 The range is 7.2~11.5μm, D 90 The thickness is 16~30μm; The content of small-particle-size carriers is 2.0~6.0% of the total weight of the powder aerosol formulation; The content of the dispersing agent is 0.1 to 0.5% of the total weight of the powder aerosol formulation.

15. The method for preparing the capsule-type inhaled powder as described in claim 14, characterized in that, The weight ratio of some dispersing aids to some small-particle-size carriers is 1:5~10.

16. The method for preparing the capsule-type inhaled powder as described in claim 14, characterized in that, The weight ratio of some dispersing aids to some small-particle-size carriers is 1:10~15.

17. The method for preparing the capsule-type inhaled powder as described in claim 14, characterized in that, The weight ratio of some dispersing agents to some small-particle-size carriers is 1:15~20.

18. The method for preparing the capsule-type inhaled powder as described in claim 14, characterized in that, In the process of mixing a portion of the dispersing agent with a portion of the small-particle-size carrier to obtain a carrier complex, the amount of the portion of the dispersing agent added is 1 / 8 to 3 / 5 of the total weight of the dispersing agent.

19. The method for preparing the capsule-type inhaled powder as described in claim 18, characterized in that, The amount of the dispersing agent added is 1 / 4 to 3 / 5 of the total weight of the dispersing agent.

20. The method for preparing the capsule-type inhaled powder as described in claim 19, characterized in that, The amount of the dispersing agent added is 1 / 2 to 3 / 5 of the total weight of the dispersing agent.

21. The method for preparing the capsule-type inhaled powder as described in claim 14, characterized in that, When performing micronization, air jet milling is used.

22. The method for preparing the capsule-type inhaled powder as described in claim 21, characterized in that, The parameters for airflow milling are: feed pressure 3~9 bar, milling pressure 2~8 bar, and feed speed 5~30 rpm.

23. The method for preparing the capsule-type inhaled powder as described in claim 14, characterized in that, The weight ratio of active ingredient intermediate I to part of the large particle size carrier is 1:1~5.

24. The method for preparing the capsule-type inhaled powder as described in claim 23, characterized in that, The weight ratio of active ingredient intermediate I to part of the large particle size carrier is 1:2~5.

25. The method for preparing the capsule-type inhaled powder as described in claim 24, characterized in that, The weight ratio of active ingredient intermediate I to part of the large particle size carrier is 1:3~5.

26. The method for preparing the capsule-type inhaled powder as described in claim 25, characterized in that, The weight ratio of active ingredient intermediate I to part of the large particle size carrier is 1:4~5.

27. The method for preparing the capsule-type inhaled powder as described in claim 14, characterized in that, A three-dimensional motion mixer was used to mix the active ingredient intermediate I with a portion of the large-particle-size carrier.

28. The method for preparing the capsule-type inhaled powder as described in claim 27, characterized in that, Mixing speed 30~90Hz, time 10~60min.

29. The method for preparing the capsule-type inhaled powder as described in claim 14, characterized in that, When the active ingredient intermediate II is mixed evenly with the remaining formulation ingredients, the remaining formulation amount of dispersant and the remaining formulation amount of large particle size carrier are first mixed under low shear to obtain a dispersant mixture, and then the remaining formulation is mixed under high shear.

30. The method for preparing the capsule-type inhaled powder as described in claim 29, characterized in that, The mixing linear velocity for high-shear mixing is 3~12 m / s, and the mixing time is 3~9 min.

31. The method for preparing the capsule-type inhaled powder as described in claim 14, characterized in that, After performing steps (1), (2), and (3) in its preparation process, an additional step for preparing the dispersant mixture is added, namely: (1) A carrier complex is obtained by mixing a portion of the dispersing agent with a portion of the small-particle-size carrier; (2) The carrier complex is mixed with the active ingredient and then micronized to obtain active ingredient intermediate I; (3) Mix the active ingredient intermediate I with a portion of the large particle size carrier evenly to obtain the active ingredient intermediate II; (4) Mix the remaining amount of dispersant and the remaining amount of large particle size carrier to obtain a dispersant mixture; (5) Mix the active ingredient intermediate II with the remaining prescription ingredients evenly.

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