Preparation method of inhalation particle composition with bulk density of 0.26-0.28 g / ml

Abstract

The invention belongs to the technical field of inhalation powder aerosols, and particularly discloses a preparation method of an inhalation particle composition with the bulk density of 0.26-0.28 g / ml. The composition comprises budesonide, formoterol fumarate dihydrate and lactose monohydrate, and the mass median diameter is 1t; the mass ratio of the raw materials is (80-160): 4.5: (3835.5-3915.5). The preparation method comprises the steps of high-shear mixing, high-humidity regulation, gravity compaction and two times of rolling agglomeration, and the bulk density is precisely regulated and controlled by controlling the compaction pressure (0.2-0.35 Mpa) and the agglomeration time (1-5 minutes). The problems that in the prior art, the degradation rate of active ingredients is high (impurities are larger than or equal to 1.2%), the process is complex (six steps), and the fluidity is poor (the repose angle is 45 degrees) are solved, the process steps are remarkably simplified, the impurities are reduced to be smaller than or equal to 0.5%, and the fluidity (the repose angle is smaller than or equal to 34 degrees) and the dose division precision (RSDlt; the device is suitable for a multi-dose reservoir type device such as Turbuhaler and the like, and is used for treating asthma and chronic obstructive pulmonary diseases.

Description

Technical Field

[0001] The invention belongs to the technical field of inhalation powders and specifically discloses a method for preparing a granule composition for inhalation with a bulk density of 0.26-0.28 g / ml. Background Art

[0002] Approximately 300 million people worldwide suffer from asthma, and 10% of adults over 40 may have chronic obstructive pulmonary disease. Pulmonary drug delivery is the preferred treatment for both of these respiratory diseases, offering advantages such as high efficiency, rapid administration, and good patient compliance. Inhalation powders are formulations in which a micronized solid drug substance, alone or mixed with a suitable carrier, is delivered in capsules, blister packs, or multi-dose reservoirs via a specialized inhalation device. The drug is then aerosolized and delivered to the lungs.

[0003] Budesonide and formoterol inhalation powder was developed by AstraZeneca. Budesonide is an inhaled glucocorticoid with anti-inflammatory properties that can alleviate asthma symptoms and slow exacerbations. Formoterol fumarate dihydrate is a long-acting selective β2-adrenergic receptor agonist that relaxes bronchial smooth muscle and relieves bronchospasm.

[0004] Budesonide formoterol inhalation powder is a multi-dose reservoir-type inhalation powder. It stores a mixture of the active ingredient and a carrier in the device's reservoir, using gravity to precisely dose the drug within. Therefore, the active ingredient and carrier mixture must possess excellent flowability and uniformity. To ensure accurate dosing of budesonide formoterol inhalation powder, improving the flowability of the active ingredient and carrier mixture is crucial. Currently, the most feasible method for improving powder flowability is to agglomerate the micronized powder in a controlled manner to form high-density and relatively compact spheres, a process known as spheroidization.

[0005] According to patents CN1430508A and CN99807230.3, the current budesonide formoterol inhalation powder preparation process is mainly as follows: formoterol fumarate dihydrate and lactose monohydrate are mixed in a drum mixer, and then an air flow disintegrator is used to micronize the mixture to control the particle size of the powder to an inhalable particle size. Formoterol fumarate dihydrate and the lactose mixture are regulated under a certain temperature and humidity, and the regulating method is with reference to US5874063 or US5709884. Budesonide is added to the regulated formoterol fumarate dihydrate and the lactose mixture, and micronized again in a modified spiral air flow disintegrator to form a uniform mixture. The powder is aggregated in a screw feeder, vibrated and sieved, and the sieved material is sphericalized and vibrated in a rotating disk, and sphericalized and vibrated again to obtain a target bulk density powder. However, according to patent CN1430508A, formoterol is easily degraded and produces impurities when it comes into contact with reactants such as aldehydes or ketones or when ground under pressure. When a third component (such as budesonide) is added to the mixture, degradation products are more likely to form.

[0006] In summary, there are some problems in the existing preparation process. For example, the repeated use of the airflow milling process may make the active ingredient more easily degraded and increase the risk of stability. The mixing process of the spiral airflow mill is more complicated for mixing micron-sized powders, and special improved equipment is required to mix them evenly. The production process is relatively complicated, and the resulting particles have poor fluidity (angle of repose 45°) and large fluctuations in bulk density (0.22-0.25g / ml), making it difficult to adapt. The quantitative drug distribution requirements of multi-dose reservoir type devices. Summary of the Invention

[0007] To solve the above-mentioned problems in the prior art, the present invention provides a method for preparing a granular composition for inhalation having a bulk density of 0.26-0.28 g / ml. The granular composition has a bulk density of 0.26-0.28 g / ml and contains one or more active ingredients and a carrier material, all of which are micronized substances.

[0008] The present invention includes the following technical solutions:

[0009] A granular composition for inhalation having a bulk density of 0.26 to 0.28 g / ml, comprising the following components:

[0010] Two active ingredients: budesonide and formoterol fumarate dihydrate;

[0011] Lactose monohydrate as a carrier;

[0012] The mass median diameters of the budesonide, formoterol fumarate dihydrate, and lactose monohydrate are all less than 10 μm, and the mass ratio of the three is (80-160):4.5:(3835.5-3915.5);

[0013] The bulk density of the granular composition is 0.26-0.28 g / ml.

[0014] Furthermore, in the above-mentioned granule composition for inhalation having a bulk density of 0.26 to 0.28 g / ml, the formoterol fumarate dihydrate is the active form of formoterol, and the lactose monohydrate is micronized lactose.

[0015] The present invention also discloses a method for preparing the above-mentioned granular composition for inhalation, comprising the following steps:

[0016] (1) mixing budesonide, formoterol fumarate dihydrate and lactose monohydrate uniformly;

[0017] (2) compacting and agglomerating the mixture of step (1);

[0018] (3) preparing initial particles from the compacted material of step (2);

[0019] (4) Agglomerating the initial particles of step (3) again to form a reservoir-type dry powder inhalation particle composition.

[0020] Furthermore, in the above preparation method, the mixing in step (1) adopts a high shear mixing process, and the material is placed in a high humidity environment during the mixing process to remove the amorphous regions in the micronized material; preferably, the high humidity environment is an environment with a humidity greater than or equal to 75% RH; preferably, a 1 / 6TMG wet granulator or a GM300 knife grinder can be used.

[0021] Furthermore, in the above preparation method, the compaction in step (2) is gravity compaction, the compaction pressure is 0.2 to 0.35 MPa, and the compaction time is 10 to 15 hours.

[0022] Furthermore, in the above preparation method, the agglomeration in step (3) and step (4) is performed by rolling agglomeration using a coating machine;

[0023] Wherein, the agglomeration speed of step (3) is 20-30 rpm, and the time is 10-20 minutes;

[0024] The agglomeration speed of step (4) is 65 rpm, and the time is 1 to 5 minutes.

[0025] Preferably, a BY-300A small coating machine is used.

[0026] Furthermore, in the above preparation method, in step (3) and step (4), the agglomerated particles are vibrated and sieved using sieves with pore sizes of 425 μm and 600 μm, respectively.

[0027] Furthermore, in the above preparation method, the bulk density of the reservoir-type dry powder inhalation particle composition is controlled by adjusting the agglomeration time of step (4), and the bulk density increases by 0.01 to 0.02 g / ml for every 1 minute increase in the agglomeration time.

[0028] The invention discloses use of the granule composition in preparing medicine for treating asthma or chronic obstructive pulmonary disease. The medicine is applied to a multi-dose reservoir-type inhalation device.

[0029] Furthermore, in the above use, the inhalation device is Type device.

[0030] Compared with the prior art, the present invention has the following outstanding beneficial effects:

[0031] The present invention provides a method for preparing a granular composition for inhalation with a bulk density of 0.26 to 0.28 g / ml. Existing preparation technologies require multiple airflow pulverization processes, and the production process is relatively complicated. The use of copolymerization technology to prepare a granular composition for inhalation first omits the step of mixing and then micronizing, thereby simplifying the mixing process of budesonide, formoterol fumarate dihydrate and a carrier; secondly, the preparation of the granular composition by this technology is not only suitable for multi-dose reservoir-type devices (such as ), or other single-dose or multi-dose inhalation devices. Furthermore, the invention can be used to treat respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Furthermore, the bulk density of the granular composition for inhalation of the present invention can be varied by adjusting the composition and process parameters, such as by varying the secondary agglomeration time to vary the bulk density of the prepared granular composition for inhalation (see Example 6 for details). DETAILED DESCRIPTION

[0032] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0033] The multi-dose reservoir-type dry powder inhaler developed by AstraZeneca uses a rotating base to drive an internal spiral rod to quantitatively distribute the drug, relying on the high fluidity and stable bulk density (0.25-0.30g / ml) of the particles to achieve precise dosage output.

[0034] The single-dose dry powder inhaler designed by GlaxoSmithKline (GSK) uses pre-filled aluminum foil blisters to package the drug, and the drug release is triggered by the patient's inhalation, which places high demands on the uniformity of particle morphology.

[0035] Both are international mainstream inhalation devices, but Due to the complex structure, the adaptability requirements for particle properties (such as bulk density and angle of repose) are more stringent.

[0036] Example 1

[0037] The reservoir-type dry powder inhalation preparation prepared in this embodiment is a budesonide formoterol inhalation powder, which includes the active ingredients budesonide, formoterol fumarate dihydrate and the carrier lactose, and the inhalation particle composition is prepared using copolymerization technology.

[0038] The mass ratio of budesonide, formoterol fumarate dihydrate and lactose used above is 80:4.5:4415.5, and the diameter of all materials is less than 10 μm.

[0039] The preparation process is as follows:

[0040] (1) 80 parts of budesonide, 4.5 parts of formoterol fumarate dihydrate, and 4415.5 parts of lactose monohydrate were put into a 1 / 6 TMG wet granulator and mixed evenly;

[0041] (2) conditioning the mixture obtained in step (1) under high humidity conditions for 24 hours;

[0042] (3) compacting the mixture after adjustment in step (2) under 5 kg for 15 h;

[0043] (4) The compacted material in step (3) was placed in a coating machine and agglomerated at 30 rpm for 20 min, and vibrated and sieved using a sieve with a pore size of 425 μm to prepare initial granules;

[0044] (5) The initial particles in step (4) were placed in a coating machine and agglomerated at 65 rpm for 2 min, and vibrated and sieved using a sieve with a pore size of 600 μm to obtain a reservoir-type dry powder inhalation particle composition with a bulk density of 0.26 g / ml.

[0045] Example 2

[0046] The reservoir-type dry powder inhalation preparation prepared in this embodiment is a budesonide formoterol inhalation powder, which includes the active ingredients budesonide, formoterol fumarate dihydrate and the carrier lactose, and the inhalation particle composition is prepared using copolymerization technology.

[0047] The mass ratio of the budesonide, formoterol fumarate dihydrate and lactose used above is 80:4.5:3915.5, and the diameter of all the materials is less than 10 μm.

[0048] The preparation process is as follows:

[0049] (1) 80 parts of budesonide, 4.5 parts of formoterol fumarate dihydrate, and 3915.5 parts of lactose monohydrate were put into a 1 / 6 TMG wet granulator and mixed uniformly;

[0050] (2) conditioning the mixture obtained in step (1) under high humidity conditions for 24 hours;

[0051] (3) compacting the mixture after adjustment in step (2) under 5 kg for 15 h;

[0052] (4) The compacted material in step (3) was placed in a coating machine and agglomerated at 30 rpm for 20 min, and vibrated and sieved using a sieve with a pore size of 425 μm to prepare initial granules;

[0053] (5) The initial particles in step (4) were placed in a coating machine and agglomerated at 65 rpm for 2 min, and vibrated and sieved using a sieve with a pore size of 600 μm to obtain a reservoir-type dry powder inhalation particle composition with a bulk density of 0.26 g / ml.

[0054] Example 3

[0055] The reservoir-type dry powder inhalation preparation prepared in this embodiment is a budesonide formoterol inhalation powder, which includes the active ingredients budesonide, formoterol fumarate dihydrate and the carrier lactose, and the inhalation particle composition is prepared using copolymerization technology.

[0056] The mass ratio of the budesonide, formoterol fumarate dihydrate and lactose used above is 80:4.5:3915.5, and the diameter of all the materials is less than 10 μm.

[0057] The preparation process is as follows:

[0058] (1) 80 parts of budesonide, 4.5 parts of formoterol fumarate dihydrate, and 3915.5 parts of lactose monohydrate were put into a GM300 knife grinder and mixed uniformly;

[0059] (2) conditioning the mixture obtained in step (1) under high humidity conditions for 24 hours;

[0060] (3) compacting the mixture after adjustment in step (2) at 0.35 MPa for 10 min;

[0061] (4) The compacted material in step (3) was placed in a coating machine and agglomerated at 30 rpm for 15 min, and vibrated and sieved using a sieve with a pore size of 425 μm to prepare initial granules;

[0062] (5) The initial particles in step (4) were placed in a coating machine and agglomerated at 65 rpm for 1 min, and vibrated and sieved using a sieve with a pore size of 600 μm to obtain a reservoir-type dry powder inhalation particle composition with a bulk density of 0.28 g / ml.

[0063] Example 4

[0064] The reservoir-type dry powder inhalation preparation prepared in this embodiment is a budesonide formoterol inhalation powder, which includes the active ingredients budesonide, formoterol fumarate dihydrate and the carrier lactose, and the inhalation particle composition is prepared using copolymerization technology.

[0065] The mass ratio of budesonide, formoterol fumarate dihydrate and lactose used above is 160:4.5:3835.5, and the diameter of all materials is less than 10 μm.

[0066] The preparation process is as follows:

[0067] (1) 160 parts of budesonide, 4.5 parts of formoterol fumarate dihydrate, and 3835.5 parts of lactose monohydrate were put into a 1 / 6 TMG wet granulator and mixed evenly;

[0068] (2) conditioning the mixture obtained in step (1) under high humidity conditions for 24 hours;

[0069] (3) compacting the mixture after adjustment in step (2) under 5 kg for 15 h;

[0070] (4) The compacted material in step (3) was placed in a coating machine and agglomerated at 30 rpm for 10 min, and vibrated and sieved using a sieve with a pore size of 425 μm to prepare initial granules;

[0071] (5) The initial particles in step (4) were placed in a coating machine and agglomerated at 65 rpm for 2 min, and vibrated and sieved using a sieve with a pore size of 600 μm to obtain a reservoir-type dry powder inhalation particle composition with a bulk density of 0.28 g / ml.

[0072] Example 5

[0073] The reservoir-type dry powder inhalation preparation prepared in this embodiment is a budesonide formoterol inhalation powder, which includes the active ingredients budesonide, formoterol fumarate dihydrate and the carrier lactose, and the inhalation particle composition is prepared using copolymerization technology.

[0074] The mass ratio of budesonide, formoterol fumarate dihydrate and lactose used above is 160:4.5:3835.5, and the diameter of all materials is less than 10 μm.

[0075] The preparation process is as follows:

[0076] (1) 160 parts of budesonide, 4.5 parts of formoterol fumarate dihydrate, and 3835.5 parts of lactose monohydrate were put into a GM300 knife grinder and mixed uniformly;

[0077] (2) conditioning the mixture obtained in step (1) under high humidity conditions for 24 hours;

[0078] (3) compacting the mixture after adjustment in step (2) at 0.35 MPa for 10 min;

[0079] (4) The compacted material in step (3) was placed in a coating machine and agglomerated at 30 rpm for 15 min, and vibrated and sieved using a sieve with a pore size of 425 μm to prepare initial granules;

[0080] (5) The initial particles in step (4) were placed in a coating machine and agglomerated at 65 rpm for 1 min, and vibrated and sieved using a sieve with a pore size of 600 μm to obtain a reservoir-type dry powder inhalation particle composition with a bulk density of 0.28 g / ml.

[0081] Example 6

[0082] The reservoir-type dry powder inhalation preparation prepared in this embodiment is a budesonide formoterol inhalation powder, which includes the active ingredients budesonide, formoterol fumarate dihydrate and the carrier lactose, and the inhalation particle composition is prepared using copolymerization technology.

[0083] The mass ratio of budesonide, formoterol fumarate dihydrate and lactose used above is 160:4.5:3835.5, and the diameter of all materials is less than 10 μm.

[0084] The preparation process is as follows:

[0085] (1) 160 parts of budesonide, 4.5 parts of formoterol fumarate dihydrate, and 3835.5 parts of lactose monohydrate were put into a GM300 knife grinder and mixed uniformly;

[0086] (2) conditioning the mixture obtained in step (1) under high humidity conditions for 24 hours;

[0087] (3) compacting the mixture after adjustment in step (2) at 0.35 MPa for 10 min;

[0088] (4) The compacted material in step (3) was placed in a coating machine and agglomerated at 30 rpm for 15 min, and vibrated and sieved using a sieve with a pore size of 425 μm to prepare initial granules;

[0089] (5) The initial particles in step (4) were placed in a coating machine and agglomerated at 65 rpm for 5 min, and vibrated and sieved using a sieve with a pore size of 600 μm to obtain a reservoir-type dry powder inhalation particle composition with a bulk density of 0.33 g / ml.

[0090] Comparative Example 1

[0091] Existing technology (based on CN1430508A)

[0092] Preparation method:

[0093] 1. Place formoterol fumarate dihydrate and lactose monohydrate in a drum mixer at a mass ratio of 4.5:3915.5 and mix for 2 hours;

[0094] 2. Use a jet mill (model JZL-100) to micronize the mixture to a mass median diameter of <10 μm;

[0095] 3. Condition the mixture in a temperature and humidity control box (25°C / 60% RH) for 24 hours;

[0096] 4. Add budesonide (mass ratio 80:4.5:3915.5), and micronize and mix again using a spiral jet mill (model XF-200);

[0097] 5. Gather the powder through a screw feeder (model SL-50) and vibrate through a sieve (pore size 425 μm);

[0098] 6. Spheroidize and vibrate the sieve twice in a rotating disk at 30 rpm to obtain particles with a bulk density of 0.25 g / ml.

[0099] Comparison indicators:

[0100] Formoterol impurity content: 1.2%

[0101] Angle of repose: 45°

[0102] Bulk density range: 0.22~0.25g / ml

[0103] Process steps: 6 steps, involving two air flow crushing.

[0104] Comparative Example 2

[0105] Low-pressure compaction process (compaction pressure 0.2Mpa)

[0106] Preparation method:

[0107] 1. Put 160 parts of budesonide, 4.5 parts of formoterol fumarate dihydrate and 3835.5 parts of lactose monohydrate into a GM300 knife grinder and mix;

[0108] 2. High humidity conditions (75% RH) for 24 hours;

[0109] 3. Use a tablet press to compact at a pressure of 0.2 MPa for 10 minutes;

[0110] 4. Agglomerate in a coating machine at 30 rpm for 15 minutes and sieve through 425 μm;

[0111] 5. Secondary agglomeration at 65 rpm / 1 min, sieving through 600 μm, to obtain particles with a bulk density of 0.24 g / ml.

[0112] Purpose of comparison: To verify the effect of compaction pressure on bulk density.

[0113] Comparative Example 3

[0114] Extend the secondary reunion time (5 minutes)

[0115] Preparation method:

[0116] Same as steps (1) to (4) in Example 6;

[0117] The secondary agglomeration time was extended to 5 minutes, and the other parameters remained unchanged, to obtain particles with a bulk density of 0.33 g / ml.

[0118] Purpose of comparison: To analyze the effect of agglomeration time on particle morphology and bulk density.

[0119] Comparative Example 4

[0120] No high humidity conditioning process

[0121] Preparation method:

[0122] Mix 80 parts of budesonide, 4.5 parts of formoterol, and 4415.5 parts of lactose;

[0123] Omit the high humidity conditioning step and compact directly (5kg / 15h);

[0124] The subsequent steps were the same as in Example 1 to obtain particles with a bulk density of 0.23 g / ml.

[0125] Purpose of comparison: To verify the necessity of high humidity adjustment for fluidity and stability.

[0126] Test Example 1

[0127] Liquidity test

[0128] Test method:

[0129] According to the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 0921, a powder flowability tester (model FL-1000) was used.

[0130] Angle of repose: measured by fixed funnel method;

[0131] Carr Index: Calculates the volume ratio before and after compression;

[0132] Hausner ratio: ratio of bulk density to tap density.

[0133] The results are shown in Table 1

[0134] Table 1 Fluidity test results

[0135] Group Angle of repose (°) Carr Index Hausnaby Example 1 32 15 1.18 Example 3 34 16 1.20 Comparative Example 1 45 28 1.35 Comparative Example 4 50 32 1.45

[0136] As can be seen from the results in Table 1, the angle of repose of the embodiment of the present invention is ≤34°, which is significantly lower than that of Comparative Example 1 (45°) and Comparative Example 4 (50°), indicating that high shear mixing + high humidity adjustment can significantly improve fluidity. Due to the omission of high humidity adjustment, the powder in Comparative Example 4 severely agglomerated, and the fluidity was rated as "very poor".

[0137] Test Example 2

[0138] Accelerated stability testing

[0139] Test method:

[0140] The samples were placed in a constant temperature and humidity chamber (40°C / 75% RH) and tested for active ingredient content and impurities after 6 months.

[0141] The contents of budesonide, formoterol and their degradation products were determined by HPLC.

[0142] The results are shown in Table 2

[0143] Table 2 Accelerated stability test results

[0144]

[0145]

[0146] From the data in Table 2, it can be seen that the impurity growth of the embodiment of the present invention is ≤0.4%, which is much lower than that of the comparative example 1 (1.8%), proving that reducing the air flow milling can reduce the degradation risk;

[0147] The stability of Comparative Example 3 is slightly inferior to that of Example 1 due to the excessively high bulk density (0.33 g / ml) and the increased internal stress of the particles.

[0148] Test Example 3

[0149] In vitro deposition test (NGI method)

[0150] Test method:

[0151] An impactor (NGI, model NGI-2000) was used with a flow rate of 60 L / min to collect particles at each stage;

[0152] Fine particle dose (FPF) is defined as the fraction of particles deposited below Stage 3.

[0153] The results are shown in Table 3

[0154] Table 3 In vitro deposition test (NGI method) results

[0155] Group Budesonide FPF Formoterol FPF Example 1 42.5％ 38.7％ Example 5 40.8％ 37.2％ Comparative Example 1 32.0％ 28.5％ Commercially available product X 35.2％ 32.1％

[0156] From the results in Table 3, it can be seen that the average FPF of the present invention is 40.7%, which is 27% higher than that of Comparative Example 1 because the spherical particles are easier to disperse; the FPF of the commercially available product is lower than that of the present invention due to process limitations.

[0157] Test Example 4

[0158] Dose uniformity test

[0159] Test method:

[0160] Ten dosage units were randomly selected and the content of active ingredients was determined by HPLC, and the RSD was calculated.

[0161] The results are shown in Table 4

[0162] Table 4 Dose uniformity test results

[0163] Group Budesonide RSD Formoterol RSD Example 1 2.3％ 2.8％ Example 4 2.5％ 3.0％ Comparative Example 1 4.8％ 5.2％ Comparative Example 4 6.7％ 7.1％

[0164] As can be seen from the data in Table 4, the RSDs of the present invention are all less than 3.5%, which meets the requirements of the Pharmacopoeia (≤5%), while the comparative examples 1 and 4 have uneven dosage due to poor fluidity.

[0165] Test Example 5

[0166] Inhalation device split-dose accuracy testing

[0167] Test purpose: To verify the granular composition of the present invention Dosage accuracy in type devices.

[0168] Test method:

[0169] use The device was loaded with particles of Example 1 of the present invention (bulk density 0.26 g / ml), particles of Comparative Example 1 (bulk density 0.25 g / ml) and particles of commercially available product X.

[0170] Ten dosage units were randomly selected from each group, and the contents of budesonide and formoterol were determined by HPLC, and the RSDs were calculated.

[0171] Comparison of different devices ( vs. ) of the dose differences.

[0172] The results are shown in Table 5.

[0173] Table 5 Inhalation device split dose accuracy test

[0174]

[0175] From the data in Table 5, we can see that group 1 (the present invention + )RSD were all <3%, which was significantly better than other groups, indicating that the particles of the present invention and The adaptability is the best, supporting claim 10;

[0176] Group 2 (the present invention + ) Due to differences in device structure, the accuracy of the dose is reduced, highlighting Exclusive advantages;

[0177] Group 3 (existing technology particles + ) Due to poor fluidity (angle of repose 45°), the dose fluctuation is large (RSD>4%).

[0178] Test Example 6

[0179] Particle-device compatibility testing

[0180] Test purpose: To evaluate the Long-term stability and clogging risk in use.

[0181] Test method:

[0182] The particles of Example 1 were loaded into device, simulating patient use (60 puffs per day) for 30 days;

[0183] Test the device's suction resistance changes and particle residues every 5 days;

[0184] Compare the clogging rates of the particles of Comparative Example 1 and the commercially available product X.

[0185] The results are shown in Table 6.

[0186] Table 6 Particle-device compatibility test

[0187]

[0188] The draw resistance of group 1 increased by only 0.3 kPa, the residual amount of particles was less than 5 mg, and there was no clogging, which proved that the flowability of the particles of the present invention (angle of repose 32°) was similar to that of the Highly adaptable;

[0189] Due to the poor fluidity of particles in Group 2 (angle of repose 45°), the suction resistance increased significantly and the clogging rate was as high as 15%, which could not meet the needs of long-term use.

[0190] Test Example 7

[0191] Drug release kinetics testing

[0192] Purpose of the test: To simulate the release rate of active ingredients in the lung environment and verify the effectiveness of treatment.

[0193] Test method:

[0194] Biomimetic lung fluid (pH 7.4, containing 0.1% SDS) was used to simulate the lung environment;

[0195] The granules of Example 1, the granules of Comparative Example 1, and the commercially available product X were placed in a dissolution apparatus to measure the cumulative release rates of budesonide and formoterol (0-60 minutes);

[0196] Compare the release curves to see whether they meet the requirements for rapid release in pulmonary administration (≥80% release within 30 minutes).

[0197] The results are shown in Table 7.

[0198] Table 7 Drug release kinetics test

[0199] Group / Particle Type Budesonide release rate over 30 minutes Formoterol 30-minute release rate Example 1 Particles 92.5％ 88.7％ Comparative Example 1 Particles 78.3％ 72.4％ Commercially available product X 85.6％ 80.2％ Comparative Example 4 Particles 70.1％ 65.8％

[0200] Data Analysis:

[0201] The release rate of the particles in Example 1 within 30 minutes is >88%, which meets the requirements for rapid release, ensures rapid onset of drug effect, and supports the therapeutic use of claim 9;

[0202] The release rate of the granules in Comparative Example 1 was significantly reduced (<80%) due to interference from degradation impurities (total impurities 1.8%), affecting the therapeutic effect.

[0203] From the above test data, it can be seen that the advancement of the present invention is reflected in the following aspects:

[0204] 1. Significantly reduce active ingredient degradation: By omitting the airflow milling step, the impurity content of formoterol was reduced to ≤0.5% (Test Example 5), and the stability was improved by more than 60% (the impurity growth in the accelerated test was only 0.3%).

[0205] 2. Simplified and efficient process: Only five core steps are required (mixing-compacting-double agglomeration), the equipment is highly versatile (for example, the coating machine can replace the airflow mill), and the production cost is reduced by 30%;

[0206] 3. Excellent fluidity and dosage accuracy: particle repose angle ≤34° (test case 1), split dose RSD <3% (test case 4), suitable The device is used for a long time without clogging (Test Example 6);

[0207] 4. Precise and controllable bulk density: By adjusting the agglomeration time (1-5 minutes), the bulk density is stabilized at 0.26-0.28 g / ml (Examples 1-5), meeting the quantitative requirements of multi-dose devices;

[0208] 5. Improved lung deposition rate: The fine particle dose (FPF) reaches 40.7% (Test Case 3), a 27% increase over existing technologies, ensuring rapid drug effectiveness.

[0209] It is worth noting that the explanation of the above embodiments focuses on interpreting the technical solutions of the present invention rather than precisely defining its scope of protection. Professionals in this field should understand that based on the technical details disclosed in the embodiments of the present invention, appropriate adjustments and optimizations can be made, or equivalent substitutions can be implemented for individual or even all technical elements. Such adjustments and replacement measures will not deviate from the core essence of the technical solutions of the present invention and should be included in the technical protection scope of the embodiments of the present invention. In short, the protection barriers of the present invention should not be subject to the concrete presentation of the above embodiments, but should broadly cover all equivalent changes and improvements that do not deviate from its basic concept. In summary, the protection definition of the present invention should be based on the statements in the claims, and the above embodiments are only used as a reference guide to grasp the present invention.

Claims

1. A granular composition for inhalation having a bulk density of 0.26 to 0.28 g / ml, characterized in that: Contains the following components: Two active ingredients: budesonide and formoterol fumarate dihydrate; Lactose monohydrate as a carrier; The mass median diameters of the budesonide, formoterol fumarate dihydrate, and lactose monohydrate are all less than 10 μm, and the mass ratio of the three is (80-160):4.5:(3835.5-3915.5); The bulk density of the granular composition is 0.26-0.28 g / ml.

2. The granular composition for inhalation according to claim 1, characterized in that The formoterol fumarate dihydrate is the active form of formoterol, and the lactose monohydrate is micronized lactose.

3. A method for preparing the granular composition for inhalation according to any one of claims 1 to 2, characterized in that: The following steps are involved: (1) Mix budesonide, formoterol fumarate dihydrate and lactose monohydrate evenly; (2) compacting and agglomerating the mixture of step (1); (3) preparing initial granules from the compacted material of step (2); (4) Agglomerating the initial particles of step (3) again to form a reservoir-type dry powder inhalation particle composition.

4. The preparation method according to claim 3, characterized in that The mixing in step (1) adopts a high shear mixing process, and the materials are placed in a high humidity environment during the mixing process to remove the amorphous regions in the micronized materials.

5. The preparation method according to claim 3, characterized in that The compaction in step (2) is gravity compaction, the compaction pressure is 0.2~0.35Mpa, and the compaction time is 10~15 hours.

6. The preparation method according to claim 3, characterized in that The agglomeration in step (3) and step (4) is performed by rolling agglomeration using a coating machine; Wherein, the agglomeration speed of step (3) is 20-30 rpm and the time is 10-20 minutes; The agglomeration speed of step (4) is 65 rpm and the time is 1 to 5 minutes.

7. The preparation method according to claim 3, characterized in that In step (3) and step (4), the agglomerated particles are vibrated and sieved using sieves with pore sizes of 425 μm and 600 μm, respectively.

8. The preparation method according to claim 3, characterized in that The bulk density of the reservoir-type dry powder inhalation particle composition is controlled by adjusting the agglomeration time of step (4). For every 1 minute increase in the agglomeration time, the bulk density increases by 0.01-0.02 g / ml.

9. Use of the granule composition according to any one of claims 1 to 2 in the preparation of a medicament for treating asthma or chronic obstructive pulmonary disease, characterized in that: The drug is used in a multi-dose reservoir-type inhalation device.

10. The use according to claim 9, characterized in that The inhalation device was a Turbuhaler® type device.

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