A process for the preparation of an inhalation powder aerosol

Abstract

The present application relates to a kind of methods for preparing inhalation powder mist, which includes the step of preparing active mixed particles, wherein the preparation method of the active mixed particles includes the following steps: (1) equilibrating active substance with first additive in environment 1 with temperature of 20-40 ℃ and humidity of RH 55-85% for more than 5 hours; (2) airflow mixing the material equilibrated in step (1) to obtain mixture 1; (3) placing mixture 1 obtained in step (2) into vacuum environment with temperature of 30-130 ℃ for equilibration for more than 0.5 hours. This method requires low operation, can reduce material agglomeration, can reduce the extrusion and friction of carrier to active substance, so as to make the product have better stability.

Description

Technical Field

[0001] This invention relates to a method for preparing inhaled powder aerosols. Background Technology

[0002] Inhaled powder inhalers (DPIs) refer to preparations in which solid micronized raw materials, alone or mixed with a suitable carrier, are delivered to the lungs by a specially designed dry powder inhaler in the form of capsules, vesicles, or multi-dose reservoirs.

[0003] Currently, the active pharmaceutical ingredients in inhaled powder inhalers are generally micronized, and then the micronized material is mixed with a carrier.

[0004] It is generally believed that when the aerodynamic particle size of a drug is in the range of 1–5 μm, it can reach the peripheral airways, the most effective absorption site. Particles larger than 5 μm usually deposit in the oral cavity or pharynx, while particles smaller than 0.5 μm do not deposit and continue to move forward due to Brownian motion. It is well known that when the particle size of a material is fine, it tends to agglomerate. Chinese patent CN106604720B describes a method of co-micronizing magnesium stearate with an active ingredient to obtain mixed particles, and then exposing these mixed particles to a specific temperature and humidity to obtain the desired mixed particles. This method can avoid the agglomeration of the active ingredient and improve the stability of the inhaled powder. However, this method requires extremely precise operation; improper operation can lead to localized solvation, causing the micronized particles to clump together, thus affecting the efficacy of the powder. Summary of the Invention

[0005] In order to overcome the shortcomings of the prior art, the present invention relates to a method for preparing inhaled powder aerosols. This method has low operational requirements, can reduce material agglomeration, and can reduce the compression and friction of the carrier on the active substance, thereby giving the product better stability.

[0006] The technical solution of the present invention is as follows:

[0007] This invention provides a method for preparing an inhaled powder aerosol, the method comprising the step of preparing active mixed particles, wherein the preparation method of the active mixed particles includes the following steps:

[0008] (1) The active substance and the first additive are balanced in an environment with a temperature of 20℃-40℃ and a humidity of RH 55%-85% for more than 5 hours. This step can effectively eliminate static electricity and facilitate the next step of mixing.

[0009] (2) The material after equilibrium in step (1) is mixed by airflow to obtain mixture 1. The airflow mixing in this step can effectively cover the active substance with the first additive.

[0010] (3) Place the mixture 1 obtained in step (2) into a vacuum environment of 30℃-130℃ for more than 0.5 hours to equilibrate. This step allows the additives and active substances to be tightly bound together.

[0011] Furthermore, in step (1), the D of the active substance 90 Less than 10μm, preferably less than 6μm.

[0012] Furthermore, in step (1), the D of the first additive 90 Less than 15μm, preferably less than 8μm.

[0013] Furthermore, in step (1), the mass ratio of the first additive to the active substance is 1%-200%, preferably 2%-80%.

[0014] Furthermore, in step (1), the active substance or the first additive is one or more components.

[0015] Furthermore, in step (1), the first additive is selected from one or more of magnesium stearate, lactose, and leucine.

[0016] Furthermore, in step (2), the pressure of the airflow mixing is 0.05-0.3 MPa.

[0017] Furthermore, in step (3), the temperature of the vacuum environment is 30℃-80℃.

[0018] Furthermore, the method also includes the step of mixing the prepared active mixed particles with a carrier or a second additive or other active substances.

[0019] Furthermore, the carrier is one or more of lactose and leucine.

[0020] Furthermore, the second additive is selected from one or more of magnesium stearate, lactose, and leucine.

[0021] Furthermore, the active ingredient is a β2-adrenergic receptor agonist selected from indacaterol and vilanterol.

[0022] Furthermore, the active ingredient is an anticholinergic bronchodilator selected from glycopyrronium bromide and umemetium bromide.

[0023] Furthermore, the active ingredient is a corticosteroid selected from mometasone and fluticasone.

[0024] Compared with the prior art, the present invention has the following beneficial technical effects:

[0025] This method provides a process for reducing material agglomeration, which can reduce material agglomeration compared to existing processes. The main reason for reducing material agglomeration in this invention is the high-strength binding of additives and active substances. During formulation, this reduces the compression and friction of the carrier on the active substance, thereby resulting in better product stability.

[0026] In the research process of this invention, different methods were employed, such as shear mixing, three-dimensional mixing, and ball milling. The results showed that, due to the small particle size of the API and additives, a large amount of API would adhere to the shear blade during shear mixing, making effective mixing impossible. During three-dimensional mixing, the API and additives could not be effectively combined. And during ball milling, the API tended to become amorphous. Ultimately, the inventors discovered that conventional processes cannot achieve a high-strength bond between additives and active substances. However, the inventors of this application found that combining airflow mixing with high-temperature vacuum can effectively achieve a high-strength bond between additives and active substances.

[0027] This invention involves highly intensive mixing of the active ingredient and additives followed by high-temperature treatment, resulting in a strong bond between the active ingredient and the additives. This strong bond reduces material agglomeration. During formulation, as the carrier mixes with the mixed particles (the highly bonded active ingredient and additives) in this invention's process, the additives effectively protect the active ingredient, reducing friction and compression of the API by the carrier, and decreasing the formation of unstable API crystal forms. Consequently, the formulation exhibits slower impurity growth in stability studies, improving the stability of the active ingredient in inhaled formulations. Example

[0028] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the contents of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0029] Example 1

[0030] Example 1-1

[0031] Micronized indacaterol maleate (D) was obtained through an air jet milling process. 90 =5.1μm)10g and magnesium stearate0.5g (D 90=10.5μm). Micronized indacaterol and magnesium stearate were placed in a tray and kept at 20℃ / RH85% for 72 hours. The samples were then removed. The equilibrated samples were sieved in incremental increments and mixed using a J20 air jet mixer at a pressure of 0.1 MPa for 15 minutes to obtain mixture 1. Mixture 1 was then placed in a vacuum drying oven at 30℃ for 2 hours to obtain mixture 2 (i.e., active mixed granules). Mixture 2 was mixed with 1 kg of lactose (ML001) in a wet granulator at a speed of 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was then encapsulated with a filling amount of 25 mg to obtain the capsule intermediate.

[0032] Mixture 2 was subjected to stability studies at 30°C / 65% RH, and the particle size of the samples was determined. The capsule intermediate was subjected to stability studies in a 60°C stability chamber, and the samples were analyzed for related substances.

[0033] Examples 1-2

[0034] Micronized indacaterol maleate (D) was obtained through an air jet milling process. 90 =5.1μm)10g and magnesium stearate0.5g (D 90 =10.5μm). Micronized indacaterol and magnesium stearate were placed in a tray and kept at 20℃ / RH85% for 72 hours. The samples were then removed. The equilibrated samples were three-dimensionally mixed to obtain mixture 1. Mixture 1 was placed in a vacuum drying oven at 30℃ for 2 hours to obtain mixture 2 (i.e., active mixed granules). Mixture 2 was mixed with 1 kg of lactose (ML001) in a wet granulator at a mixing speed of 12 r / s for 10 min to obtain mixture 3. Mixture 3 was then encapsulated with a filling amount of 25 mg to obtain the capsule intermediate.

[0035] Mixture 2 was subjected to stability studies at 30°C / 65% RH, and the particle size of the samples was determined. The capsule intermediate was subjected to stability studies in a 60°C stability chamber, and the samples were analyzed for related substances.

[0036] Examples 1-3

[0037] Micronized indacaterol maleate (D) was obtained through an air jet milling process. 90 =5.1μm)10g and magnesium stearate0.5g (D 90=10.5μm). The micronized indacaterol and magnesium stearate samples were sieved in equal increments to obtain mixture 1. Mixture 1 was placed in a vacuum drying oven at 30℃ for 2 hours to obtain mixture 2. Mixture 2 was then mixed with 1 kg of lactose (ML001) in a wet granulator at 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was then encapsulated with a filling amount of 25 mg to obtain the capsule intermediate.

[0038] Mixture 2 was subjected to stability studies at 30°C / 65% RH, and the particle size of the samples was determined. The capsule intermediate was subjected to stability studies in a 60°C stability chamber, and the samples were analyzed for related substances.

[0039] Examples 1-4

[0040] Micronized indacaterol maleate (D) was obtained through an air jet milling process. 90 =5.1μm)10g and magnesium stearate0.5g (D 90 =10.5μm). Micronized indacaterol and magnesium stearate were placed in a tray and kept at 20℃ / RH85% for 72 hours. The samples were then removed. The equilibrated samples were sieved in incremental increments and mixed using a J20 air jet mixer at a pressure of 0.1 MPa for 15 minutes to obtain mixture 2. Mixture 2 was then mixed with 1 kg of lactose (ML001) in a wet granulator at a speed of 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was then encapsulated with a filling amount of 25 mg to obtain the capsule intermediate.

[0041] Mixture 2 was subjected to stability studies at 30°C / 65% RH, and the particle size of the samples was determined. The capsule intermediate was subjected to stability studies in a 60°C stability chamber, and the samples were analyzed for related substances.

[0042] Examples 1-5

[0043] Micronized indacaterol maleate (D) was obtained through an air jet milling process. 90 =5.1μm)10g and magnesium stearate0.5g (D 90 =10.5μm). Micronized indacaterol and magnesium stearate were placed in a sample and sieved in equal increments to obtain mixture 2. Mixture 2 was then mixed with 1 kg of lactose (ML001) in a wet granulator at a mixing speed of 12 r / s for 10 min to obtain mixture 3. Mixture 3 was then encapsulated with a filling amount of 25 mg to obtain the capsule intermediate.

[0044] Mixture 2 was subjected to stability studies at 30°C / 65% RH, and the particle size of the samples was determined. The capsule intermediate was subjected to stability studies in a 60°C stability chamber, and the samples were analyzed for related substances.

[0045] Table 1. Particle size study of mixtures 2 from Examples 1-1 to 1-5 at 30°C / 65% RH

[0046]

[0047] Table 2. Stability study of capsule intermediates in a 60°C stability chamber (related substances)

[0048]

[0049]

[0050] Example 2

[0051] Micronized methyl ammonium bromide (D) was obtained by air jet milling process. 90 =7.0μm)10g, Vilanterol (D 90 =5.1μm), fluticasone furoate (D 90 =4.0μm) and magnesium stearate 20g (D 90 =6.0μm). The material was placed in a tray and placed at 30℃ / RH65% for 24 hours, after which the sample was removed. The equilibrated sample was sieved in equal increments and mixed with air using a J20 at a mixing pressure of 0.3 MPa for 15 minutes to obtain mixture 1. Mixture 1 was placed in a vacuum drying oven at 30℃ for 48 hours to obtain mixture 2. Mixture 2 was mixed with lactose (ML001, 1 kg) in a wet granulator at a mixing speed of 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was then filled into capsules with a filling amount of 25 mg to obtain the capsule intermediate.

[0052] Example 3-1

[0053] Micronized glycopyrronium bromide (D) was obtained by air jet milling process. 90 =7.0μm)10g and lactose monohydrate40g (D 90=6.0μm). The material was placed in a tray and placed at 40℃ / RH55% for 10 hours, after which the sample was removed. The equilibrated sample was sieved in equal increments and mixed with air using a J20 at a mixing pressure of 0.2 MPa for 15 minutes to obtain mixture 1. Mixture 1 was placed in a vacuum drying oven at 80℃ for 1 hour to obtain mixture 2. Mixture 2, 1 kg of leucine and 30 g of magnesium stearate were placed in a wet granulator and mixed at a mixing speed of 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was filled into capsules with a filling amount of 25 mg to obtain the capsule intermediate. The capsule intermediate was placed in a 60℃ stability chamber for stability studies, and the sample was analyzed for related substances.

[0054] Example 3-2

[0055] Micronized glycopyrronium bromide (D) was obtained by air jet milling process. 90 =7.0μm)10g, and lactose monohydrate 40g (D 90 =6.0μm). The material was placed in a tray and placed at 40℃ / RH55% for 10 hours, after which the sample was removed. The equilibrated sample was sieved in equal increments and mixed in a three-dimensional mixer at a mixing speed of 23 r / min for 30 min to obtain mixture 1. Mixture 1 was placed in a vacuum drying oven at 80℃ for 1 hour to obtain mixture 2. Mixture 2, 1 kg of leucine and 30 g of magnesium stearate were placed in a wet granulator and mixed at a mixing speed of 12 r / s for 10 min to obtain mixture 3. Mixture 3 was capsule-filled with a filling amount of 25 mg to obtain the capsule intermediate. The capsule intermediate was placed in a 60℃ stability chamber for stability studies, and the sample was analyzed for related substances.

[0056] Example 3-3

[0057] Micronized glycopyrronium bromide (D) was obtained by air jet milling process. 90 =7.0μm)10g, and lactose monohydrate 40g (D 90=6.0μm). The material was placed in a tray and placed at 40℃ / RH55% for 10 hours, after which the sample was removed. The equilibrated sample was sieved in equal increments and mixed in a ball mill with agate grinding balls. The mixing speed was 150 r / min and the mixing time was 5 min to obtain mixture 1. Mixture 1 was placed in a vacuum drying oven and dried at 80℃ for 1 hour to obtain mixture 2. Mixture 2, 1 kg of leucine and 30 g of magnesium stearate were placed in a wet granulator and mixed at 12 r / s for 10 min to obtain mixture 3. Mixture 3 was filled into capsules with a filling amount of 25 mg to obtain the capsule intermediate. The capsule intermediate was placed in a 60℃ stability chamber for stability studies, and the sample was analyzed for related substances.

[0058] Table 3. Stability study of capsule intermediates in a 60°C stability chamber (related substances)

[0059] Total impurities (%) Example 3-1 Example 3-2 Example 3-3 0 days 1.2 2.5 3.0 1 day 1.5 3.0 3.4 3 days 1.5 3.7 4.1 7 days 2.0 4.3 4.7

[0060] Example 4-1

[0061] Micronized mometasone furoate (D) was obtained by air jet milling process. 90 =3.2μm)10g and lactose monohydrate40g (D 90 =6.0μm). The material was placed in a tray and placed at 40℃ / RH55% for 10 hours, after which the sample was removed. The equilibrated sample was sieved in equal increments and mixed using a J20 air jet mixer at a pressure of 0.05 MPa for 15 minutes to obtain mixture 1. Mixture 1 was placed in a vacuum drying oven at 80℃ for 1 hour to obtain mixture 2. Mixture 2 was mixed with 1 kg of lactose in a wet granulator at a speed of 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was then capsule-filled with a filling amount of 25 mg to obtain a capsule intermediate. The capsule intermediate was placed in a 60℃ stability chamber for stability studies, and related substances were analyzed.

[0062] Example 4-2

[0063] Micronized mometasone furoate (D) was obtained by air jet milling process. 90 =3.2μm)10g and lactose monohydrate40g (D 90=6.0μm). The material was placed in a tray and placed at 40℃ / RH55% for 10 hours, after which the sample was removed. The equilibrated sample was sieved and mixed in equal increments using a J20 air jet mixer at a pressure of 0.3 MPa for 15 minutes to obtain mixture 1. Mixture 1 was then placed in a vacuum drying oven at 80℃ for 1 hour to obtain mixture 2. Mixture 2 was then mixed with 1 kg of lactose in a wet granulator at a speed of 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was then capsule-filled with a filling amount of 25 mg to obtain a capsule intermediate. The capsule intermediate was then placed in a 60℃ stability chamber for stability studies, and related substances were analyzed on the sample.

[0064] Example 4-3

[0065] 10g of micronized mometasone furoate (D90 = 3.2μm) and 40g of lactose monohydrate were obtained by air jet milling. 90 =6.0μm). The material was placed in a tray and placed at 40℃ / RH55% for 10 hours, after which the sample was removed. The equilibrated sample was sieved and mixed in equal increments using a J20 air jet mixer at a pressure of 0.6 MPa for 15 minutes to obtain mixture 1. Mixture 1 was then placed in a vacuum drying oven at 80℃ for 1 hour to obtain mixture 2. Mixture 2 was then mixed with 1 kg of lactose in a wet granulator at a speed of 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was then capsule-filled with a filling amount of 25 mg to obtain a capsule intermediate. The capsule intermediate was then placed in a 60℃ stability chamber for stability studies, and related substances were analyzed.

[0066] Example 4-4

[0067] 10g of micronized mometasone furoate (D90 = 3.2μm) and 40g of lactose monohydrate were obtained by air jet milling. 90=6.0μm). The material was placed in a tray and placed at 40℃ / RH55% for 10 hours, after which the sample was removed. The equilibrated sample was sieved and mixed in equal increments using a J20 air jet mixer at a pressure of 0.3 MPa for 15 minutes to obtain mixture 1. Mixture 1 was then placed in a vacuum drying oven at 130℃ for 1 hour to obtain mixture 2. Mixture 2 was then mixed with 1 kg of lactose in a wet granulator at a speed of 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was then capsule-filled with a filling amount of 25 mg to obtain a capsule intermediate. The capsule intermediate was then placed in a 60℃ stability chamber for stability studies, and related substances were analyzed.

[0068] Examples 4-5

[0069] 10g of micronized mometasone furoate (D90 = 3.2μm) and 40g of lactose monohydrate were obtained by air jet milling. 90 =6.0μm). The material was placed in a tray and placed at 40℃ / RH55% for 10 hours, after which the sample was removed. The equilibrated sample was sieved in equal increments and mixed with air using a J20 at a mixing pressure of 0.3 MPa for 15 minutes to obtain mixture 1. Mixture 1 was placed in a vacuum drying oven at 160℃ for 1 hour to obtain mixture 2. Mixture 2 was mixed with 1 kg of lactose in a wet granulator at a mixing speed of 12 r / s for 10 minutes to obtain mixture 3. Mixture 3 was capsule-filled with a filling amount of 25 mg to obtain a capsule intermediate. The capsule intermediate was placed in a 60℃ stability chamber for stability studies, and the sample was analyzed for related substances.

[0070] Table 4. Stability study of capsule intermediates in a 60°C stability chamber (related substances)

[0071]

Claims

1. A process for the preparation of an inhalation powder aerosol, which process comprises the step of preparing a mixture of active particles, wherein, The method for preparing the active mixed granules comprises the following steps: (1) equilibrating the active substance and the first additive in an environment with a temperature of 20-40°C and a humidity of RH 55-85% for more than 5 hours; (2) air-flow mixing the equilibrated material of step (1) to obtain a mixture 1; (3) placing the mixture 1 obtained in step (2) in a vacuum environment with a temperature of 30-130°C for equilibration for more than 0.5 hours; wherein the D50 of the active substance is less than 10 pm; and 90 less than 10 pm; D of the first additive is less than 15 pm 90 less than 15 pm; The first additive is selected from one or more of magnesium stearate, lactose and leucine; The active ingredient is a β2 adrenergic receptor agonist, an anticholinergic bronchodilator or a corticosteroid; selected from indacaterol, vilanterol, glycopyrronium bromide, umeclidinium bromide, mometasone and fluticasone.

2. The method of claim 1, wherein, In step (1), the D50 of the active substance is less than 6 μm. 90 less than 6 μm.

3. The method of claim 1, wherein, In step (1), the D50 of the first additive is less than 8 pm. 90 less than 8 pm.

4. The method of claim 1, wherein, In step (1), the mass ratio of the first additive to the active substance is 1%-200%.

5. The method of claim 1, wherein, In step (1), the mass ratio of the first additive to the active substance is 2%-80%.

6. The method of claim 1, wherein, In step (1), the active substance or the first additive is one or more components.

7. The method of any one of claims 1 to 6, wherein, In step (2), the pressure of the air-flow mixing is 0.05-0.3 MPa.

8. The method of any one of claims 1 to 6, wherein, In step (3), the temperature of the vacuum environment is 30-80°C.

9. The method of any one of claims 1 to 6, wherein, The method further comprises a step of mixing the prepared active mixed granules with a carrier or a second additive or other active substances.

10. The method of claim 9, wherein, The carrier is one or more of lactose and leucine.

11. The method of claim 9, wherein, The second additive is selected from one or more of magnesium stearate, lactose and leucine.

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