A carrier particle for an inhalation powder and an inhalation powder comprising the carrier particle

Abstract

The application discloses a carrier particle for inhalation powder, wherein the carrier is lactose, including lactose I, lactose II and lactose III, and the content of lactose I is 2.5%-15.0%, the content of lactose II is 5.0%-20.0%, and the content of lactose III is 65.0%-92.5% based on the total weight of the carrier particle; wherein the D50 of lactose I is 2-6 microns, the D50 of lactose II is 20-40 microns, and the D50 of lactose III is 60-80 microns; the carrier particle is prepared by the following method: A) first mixing lactose II and lactose III in a mixing device by high shear, then adding lactose I and mixing again by high shear to obtain mixed lactose; B) exposing the mixed lactose obtained in step A) to an environment with a temperature of 30-70 DEG C and a relative humidity of 45%-85% for more than 12 hours to obtain the carrier particle. The application further discloses an inhalation dry powder preparation containing the carrier particle and an inhalation powder. The carrier particle can make the delivery dose of the inhalation powder basically consistent under different suction, thereby reducing the influence of the inhalation mode of patients on the curative effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a carrier particle for inhaled powder and its preparation method, as well as an inhaled powder containing the carrier particle. Background Technology

[0002] Aerosol of Micropowders for Inspiration, or Dry Powder Inhalations (DPIs), is a new generation of propellant-free micropowdered aerosols. It consists of a powder inhalation (or spraying) device and dry powder for inhalation or spraying. Based on the energy source, the delivery device for inhaled powder aerosols can be divided into passive and active types. Currently, commercially available inhaled powder aerosols are all passive, consisting of an air inlet, a dispersion chamber, and a mouthpiece. After the patient inhales, the powder enters the dispersion chamber, where the drug and carrier are deagglomerated by the combined action of airflow turbulence and powder impaction. The drug then enters the lungs through the airway. In this process, the patient's inspiratory airflow is the sole driving force for the powder to enter the body, thus eliminating the need for hand and respiratory coordination. This is the biggest advantage of passive inhaled aerosols, but also one of their disadvantages, as powder dispersion is greatly affected by flow rate. For example, with the Turbuhaler (a third-generation reservoir-type powder inhaler), when the maximum inspiratory flow rate is 30 L / min... -1 Increased to 60 L·min -1 When budesonide and formoterol are used, the delivery dose and microparticle dose of both drugs increase. However, for children, the elderly, and patients with cystic fibrosis, it is often difficult to achieve a large inspiratory flow rate (Gao Lei, et al. A brief analysis and comprehensive evaluation of inhaled powder delivery devices [J]. Chinese Journal of New Drugs, 2019, 28(3): 335-337). The flow rate-dependent nature of passive inhaled powders leads to poor reproducibility of delivery doses due to differences in patient usage, thus affecting efficacy.

[0003] In addition, the delivery devices for inhaled powder inhalers have diverse, sophisticated, and complex structures. The methods of using these devices also vary. Patients must receive specialized education to master the correct use of the inhalation delivery device. Lu Lei et al. investigated 100 patients each of budesonide / formoterol inhaled powder, salmeterol / fluticasone powder, and tiotropium bromide powder, and statistically analyzed the device usage after no more than three medication education sessions. The results showed that only about half of the patients could operate the device correctly after one medication education session, while about 90% of the patients could use the device correctly after three medication education sessions (Lu Lei, et al. Analysis of medication compliance survey for dry powder inhalers [J]. Strait Pharmaceutical Journal, 2021, 33(7): 119-122). If patients cannot use the inhalation device correctly, it will inevitably affect the inhalation flow rate, making it difficult for the inhaled powder inhaler to exert its therapeutic advantages. Summary of the Invention

[0004] To address the issues of inadequate drug delivery and poor reproducibility caused by variations in inhalation flow rates among patients, this invention provides a carrier particle suitable for inhaled powders at different flow rates, and an inhaled powder containing the carrier particle.

[0005] The present invention adopts the following technical solution:

[0006] A carrier particle for an inhaled powder inhaler, wherein the carrier is lactose, comprising lactose I, lactose II, and lactose III, wherein, based on the total weight of the carrier particles (100%), lactose I accounts for 2.5%–15.0%, lactose II accounts for 5.0%–20.0%, and lactose III accounts for 65.0%–92.5%; wherein the D50 of lactose I is 2–6 μm, the D50 of lactose II is 20–40 μm, and the D50 of lactose III is 60–80 μm; the carrier particle is prepared by the following method:

[0007] A) First, lactose II and lactose III are mixed in a mixing device under high shear, then lactose I is added, and then high shear mixing is performed again to obtain mixed lactose;

[0008] B) Expose the mixed lactose obtained in step A) to an environment of 30℃~70℃ and RH45%~85% for more than 12 hours to equilibrate, and the carrier particles are obtained.

[0009] Preferably, the lactose is α-lactose monohydrate (or α-lactose monohydrate).

[0010] Preferably, in step A), the rotation speed is 2-30 rpm during the two high-shear mixing processes, and each process lasts 1-30 minutes.

[0011] More preferably, in step A), the rotation speed is 4-14 rps during the two high-shear mixing processes, and each process lasts 4-12 min.

[0012] Preferably, in step B), the temperature is 30℃~45℃.

[0013] Preferably, in step B), the humidity is RH 60% to RH 80%.

[0014] A second objective of the present invention is to provide an inhalation dry powder formulation comprising the aforementioned carrier particles and one or more active ingredients.

[0015] Preferably, the D50 of the active ingredient is less than 5 μm.

[0016] Preferably, the active ingredient is selected from one or more of β2-adrenergic receptor agonists and corticosteroids.

[0017] Preferably, the β2-adrenergic receptor agonist is selected from indacaterol, formoterol, vilanterol, salmeterol, or olodaterol, or a pharmaceutically acceptable salt of indacaterol, formoterol, vilanterol, salmeterol, or olodaterol.

[0018] More preferably, the β2-adrenergic receptor agonist is salmeterol or a pharmaceutically acceptable salt thereof.

[0019] Preferably, the mass ratio of the β2-adrenergic receptor agonist to the carrier particles is 1:100 to 1:500.

[0020] Preferably, the corticosteroid is selected from budesonide, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone dipropionate, or cicosone.

[0021] More preferably, the corticosteroid is fluticasone propionate.

[0022] Preferably, the mass ratio of the corticosteroid to the carrier particles is 1:20 to 1:500.

[0023] A third objective of the present invention is to provide a method for preparing the above-mentioned inhaled dry powder formulation, comprising mixing the carrier particles and the active ingredient described in the present invention.

[0024] Preferably, the carrier particles and the active ingredient are mixed in a high-speed mixing device for 1 to 30 minutes, and the mixing speed of the mixing device is 3 to 30 rpm.

[0025] More preferably, the carrier particles and the active ingredient are mixed in a high-speed stirring device for 4 to 12 minutes, and the stirring speed of the stirring device is 6 to 16 rps.

[0026] In addition, the present invention provides an inhaled powder preparation comprising the above-mentioned dry powder formulation for inhalation and an inhalation device; wherein the dry powder formulation for inhalation is quantitatively filled in a single-dose or multi-dose container, and the inhalation device is a passive inhalation device.

[0027] The specific inhalation carrier particles provided by this invention enable inhaled powder aerosols to achieve a substantially consistent delivery dose under different inhalation forces, thereby reducing the impact of the patient's inhalation method on the therapeutic effect. Detailed Implementation

[0028] The present invention will be described below with reference to specific embodiments. Those skilled in the art will understand that these embodiments are for illustrative purposes only and do not limit the scope of the invention in any way.

[0029] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available products. The purchase channels for some of the raw materials and reagents are as follows:

[0030] α-Lactose monohydrate (purchased from DFE) with D50 values ​​of 1 μm, 4 μm, 6 μm, 8 μm, 10 μm, 30 μm, 38 μm, 40 μm, 55 μm, 70 μm, 76 μm, 80 μm, and 100 μm.

[0031] For inhaled formulations, aerodynamic particle size and its distribution are among the key quality attributes. The main indicators of aerodynamic particle size distribution include fine particle dose (FPD). The following research examples and embodiments used a next-generation impactor (NGI) method (device 3, next-generation impactor, listed in Appendix 0951 of the Chinese Pharmacopoeia 2020) to obtain the fine particle dose (FPD). Unless otherwise specified, all fine particles mentioned herein are particles with a diameter less than 5 μm.

[0032] Study Example 1: Effect of Lactose Mixing Order on Formulation FPD

[0033] The formulation of the carrier particles prepared in this study is as follows:

[0034]

[0035] 1.1 Preparation of Inhalation Dry Powder Formulation 1

[0036] Weigh out the prescribed amounts of lactose I, II, and III separately. First, add lactose II and lactose III to a wet shear mixer and mix at 8 rpm for 10 min, then let it stand appropriately. Next, add lactose I and mix at 8 rpm for 10 min, then let it stand appropriately. Then transfer it to a humidity chamber and age it at 30℃ / 80% RH for 24 h to obtain carrier particles 1. Mix carrier particles 1 with 0.38 g of micronized salmeterol (D50: below 5 μm) and 3.8 g of micronized fluticasone propionate (D50: below 5 μm) for 2 min, then transfer it to a wet shear mixer and mix at 6 rpm for 10 min to obtain inhalation dry powder formulation 1.

[0037] 1.2 Preparation of Inhalation Dry Powder Formulation 2

[0038] Weigh out the prescribed amounts of lactose I, II, and III separately. Add lactose I, II, and III to a wet shear mixer, mix at 8 rpm for 10 min, allow to stand appropriately, then transfer to a humidity chamber and age at 30℃ / 80% RH for 24 h to obtain carrier particles 2. Mix carrier particles 2 with 0.38 g of micronized salmeterol (D50: below 5 μm) and 3.8 g of micronized fluticasone propionate (D50: below 5 μm) for 2 min, transfer to a wet mixing shear mixer, mix at 6 rpm for 10 min to obtain inhalation dry powder formulation 2.

[0039] 1.3 Preparation of Inhalation Dry Powder Formulation 3

[0040] Weigh out the prescribed amounts of lactose I, II, and III separately. First, add lactose I and lactose II to a wet shear mixer and mix at 8 rpm for 10 minutes, then let it stand appropriately. Next, add lactose III and mix at 8 rpm for 10 minutes, then let it stand appropriately. Then transfer it to a humidity chamber and age it at 30℃ / 80% RH for 24 hours to obtain carrier particles 3. Mix carrier particles 3 with 0.38 g of micronized salmeterol (D50: below 5 μm) and 3.8 g of micronized fluticasone propionate (D50: below 5 μm) for 2 minutes, then transfer it to a wet shear mixer and mix at 6 rpm for 10 minutes to obtain inhalation dry powder formulation 3.

[0041] Using a new generation of cascade impactors, the FPD of inhaled dry powder formulations 1, 2 and 3 was measured at different flow rates (30 L / min, 60 L / min and 90 L / min). The inhalation device was a cyclotor. The results are shown in Table 1.

[0042] Table 1. FPD at different flow rates for the inhalation dry powder formulation prepared in Study Example 1.

[0043]

[0044] Table 1 shows that the FPD values ​​of inhaled dry powder formulation 1 are basically consistent at different flow rates, while the FPD values ​​of inhaled dry powder formulations 2 and 3 differ significantly at different flow rates. Therefore, the mixing order of lactose with different particle sizes has a significant impact on the FPD of the final inhaled formulation. It is preferable to mix lactose II (with intermediate particle size) and lactose III (with the largest particle size) first, and then add lactose I (with the smallest particle size) last.

[0045] Study Example 2: Effect of lactose particle size on formulation FPD

[0046] Weigh the prescribed amounts of lactose I, II, and III as shown in Table 2. First, add lactose II and lactose III to a wet shear mixer, mix at 10 rpm for 10 min, and let stand for a while. Then add lactose I, mix at 10 rpm for 10 min, and let stand for a while. Then transfer to a humidity chamber, age at 40℃ / RH 60% for 30 h, and remove to prepare carrier particles 4, 5, and 6. Mix the carrier particles with 0.38 g of micronized vilanterol (D50: below 5 μm) and 3.8 g of micronized fluticasone furoate (D50: below 5 μm) for 2 min, transfer to a wet shear mixer, mix at 10 rpm for 10 min, and obtain inhalation dry powder formulations 4, 5, and 6, respectively.

[0047] Using a new generation of cascade impactors, the FPD of inhaled dry powder formulations 4, 5 and 6 was measured at different flow rates (30 L / min, 60 L / min and 90 L / min). The inhalation device was a cyclotor. The results are shown in Table 3.

[0048] Table 2 Lactose formulations for carrier particles 4, 5, and 6.

[0049]

[0050] Table 3. FPD at different flow rates for the inhalation dry powder formulation prepared in Study Example 2.

[0051]

[0052] Table 3 shows that the FPD values ​​of inhaled dry powder formulation 4 are basically consistent at different flow rates, while the FPD values ​​of inhaled dry powder formulations 5 and 6 differ significantly at different flow rates. Therefore, the lactose particle size distribution has a significant impact on the FPD of the final inhaled formulation.

[0053] Study Example 3: Effect of the mass ratio of lactose I, II, and III on FPD

[0054] Weigh the prescribed amounts of lactose I, II, and III as shown in Table 4. First, add lactose II and lactose III to a wet shear mixer and mix at 14 rpm for 5 minutes, then let it stand appropriately. Next, add lactose I and mix at 14 rpm for 5 minutes, then let it stand appropriately. Then, transfer the mixture to a humidity chamber and age it at 60℃ / 40% RH for 15 hours to prepare carrier particles 7, 8, and 9. Mix the carrier particles with 0.38 g of micronized formoterol (D50: below 5 μm) and 3.8 g of micronized budesonide (D50: below 5 μm) for 2 minutes, then transfer the mixture to a wet shear mixer and mix at 16 rpm for 5 minutes to obtain inhalation dry powder formulations 7, 8, and 9.

[0055] Using a new generation of cascade impactors, the FPD of inhaled dry powder formulations 7, 8 and 9 was measured at different flow rates (30 L / min, 60 L / min and 90 L / min). The inhalation device was a cyclotor. The results are shown in Table 5.

[0056] Table 4. Lactose formulations for carrier particles 7, 8, and 9.

[0057]

[0058] Table 5. FPD at different flow rates for the inhaled dry powder formulation prepared in Study Example 3.

[0059]

[0060] Table 5 shows that the FPD values ​​of inhaled dry powder formulation 7 were basically consistent at different flow rates, while the FPD values ​​of inhaled dry powder formulations 8 and 9 differed significantly at different flow rates. Therefore, the mass ratio of lactose I, II, and III has a significant impact on the FPD of the final inhaled formulation.

[0061] Based on Examples 1 and 2, the preferred technical solution for the lactose carrier particles for inhaled powder provided by the present invention is as follows: the lactose carrier particles comprise lactose I, lactose II, and lactose III, wherein, based on the total weight of the carrier particles (100%), lactose I accounts for 2.5%–15.0%, lactose II accounts for 5.0%–20.0%, and lactose III accounts for 65.0%–92.5%; wherein the D50 of lactose I is 2–6 μm, the D50 of lactose II is 20–40 μm, and the D50 of lactose III is 60–80 μm; the carrier particles are prepared by the following method:

[0062] A) First, add lactose II and lactose III to the mixing device and mix them under high shear. Then add lactose I and mix them under high shear again to obtain the mixed lactose.

[0063] B) Expose the mixed lactose obtained in step A) to an environment of 30℃~70℃ and RH45%~85% for more than 12 hours to equilibrate, and the carrier particles are obtained.

[0064] Example 1: A dry powder for inhalation of mometasone furoate and indacaterol

[0065] The formulation of the carrier particles prepared in this embodiment is as follows:

[0066]

[0067] Weigh out the prescribed amounts of lactose I, II, and III separately. First, add lactose II and lactose III to a wet shear mixer and mix at 8 rpm for 10 minutes, then let it stand appropriately. Next, add lactose I and mix at 8 rpm for 10 minutes, then let it stand appropriately. Then transfer it to a humidity chamber and age it at 30℃ / 80% RH for 24 hours to obtain the carrier particles. Mix the carrier particles with 0.32 g of micronized mometasone furoate (D50: below 5 μm) and 0.69 g of micronized indacaterol (D50: below 5 μm) for 2 minutes, then transfer it to a wet shear mixer and mix at 6 rpm for 10 minutes to obtain the inhalation dry powder formulation.

[0068] Using a new generation of cascade impactors, the flow rate potential (FPD) of the inhaled dry powder formulation prepared in this embodiment was measured at different flow rates (30 L / min, 60 L / min and 90 L / min). The inhalation device was a cyclotor. The results are shown in Table 6.

[0069] Table 6. FPD at different flow rates for the inhalation dry powder formulation prepared in Example 1.

[0070]

[0071] Table 6 shows that the FPD values ​​of the inhalation dry powder formulation prepared in this embodiment are basically consistent at different flow rates. In summary, the inhalation dry powder formulations prepared using the lactose carrier particles of this invention with different active ingredients can all achieve essentially consistent FPD values ​​at the three flow rates.

[0072] In summary, the present invention provides a specific inhalation carrier that enables inhaled powder to achieve a substantially consistent delivery dose under different inhalation intensities, thereby reducing the impact of the patient's inhalation method on the therapeutic effect.

Claims

1. A carrier particle for an inhaled powder, said carrier being α-lactose monohydrate, comprising lactose I, lactose II, and lactose III, wherein, based on the total weight of the carrier particles (100%), lactose I accounts for 2.5% to 15.0%, lactose II accounts for 5.0% to 20.0%, and lactose III accounts for 65.0% to 92.5%; wherein, The D50 of lactose I is 2-6 μm, the D50 of lactose II is 20-40 μm, and the D50 of lactose III is 60-80 μm; the carrier particles are prepared by the following method: A) First, lactose II and lactose III are mixed in a mixing device under high shear, then lactose I is added, and then mixed under high shear again to obtain the mixed lactose; B) Expose the mixed lactose obtained in step A) to an environment of 30℃~45℃ and RH60%~80% for more than 12 hours to equilibrate, and the carrier particles are obtained.

2. The carrier particles according to claim 1, characterized in that, In step A), the rotation speed is 2~30 rpm during the two high-shear mixing processes, and each process lasts 1~30 minutes.

3. The carrier particles according to claim 2, characterized in that, In step A), the rotation speed is 4~14 rps during the two high-shear mixing processes, and each process lasts 4~12 min.

4. An inhalation dry powder formulation comprising carrier particles as described in any one of claims 1 to 3, and further comprising one or more active ingredients.

5. The inhalation dry powder formulation according to claim 4, characterized in that, The active ingredient has a D50 of less than 5 μm.

6. The inhalation dry powder formulation according to claim 5, characterized in that, The active ingredient is selected from one or more of β2-adrenergic receptor agonists and corticosteroids.

7. The inhalation dry powder formulation according to claim 6, characterized in that, The β2-adrenergic receptor agonist is selected from indacaterol, formoterol, vilanterol, salmeterol, or olodaterol, or a pharmaceutically acceptable salt of indacaterol, formoterol, vilanterol, salmeterol, or olodaterol.

8. The inhalation dry powder formulation according to claim 7, characterized in that, The β2-adrenergic receptor agonist is salmeterol or a pharmaceutically acceptable salt thereof.

9. The inhalation dry powder formulation according to claim 7 or 8, characterized in that, The mass ratio of the β2-adrenergic receptor agonist to the carrier particles is 1:100 to 1:

500.

10. The inhalation dry powder formulation according to claim 6, characterized in that, The corticosteroids are selected from budesonide, fluticasone propionate, fluticasone furoate, mometasone furoate, beclomethasone dipropionate, or cicosone.

11. The inhalation dry powder formulation according to claim 10, characterized in that, The corticosteroid is fluticasone propionate.

12. The inhalation dry powder formulation according to claim 10 or 11, characterized in that, The mass ratio of the corticosteroid to the carrier particles is 1:20 to 1:

500.

13. A method for preparing an inhalation dry powder formulation according to any one of claims 4 to 12, comprising mixing a carrier particle according to any one of claims 1 to 3 and an active ingredient; wherein the active ingredient is as defined in any one of claims 5 to 12.

14. The preparation method according to claim 13, characterized in that, The carrier particles and the active ingredient are mixed in a high-speed mixing device for 1 to 30 minutes, and the mixing speed of the mixing device is 3 to 30 rps.

15. The preparation method according to claim 14, characterized in that, The carrier particles and the active ingredient are mixed in a high-speed mixing device for 4 to 12 minutes, and the mixing speed of the mixing device is 6 to 16 rps.

16. An inhaled powder formulation comprising an inhaled dry powder formulation according to any one of claims 4 to 12 or the inhaled dry powder formulation directly obtained by the preparation method according to any one of claims 13 to 15, further comprising an inhalation device; wherein the inhaled dry powder formulation is quantitatively filled in a single-dose or multi-dose container, and the inhalation device is a passive inhalation device.

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