Method for controlling grain size of lactose

Abstract

The invention provides a preparation method of lactose with controllable particle size, which comprises the following steps: firstly, controlling the initial particle size of lactose and removing residual protein, microorganisms and endotoxin in the lactose in a crystallization manner; the whole control method is simple and convenient to operate, adopts a mode of combining crystallization and crushing, has the advantages of low cost, environmental protection, high continuity, cost reduction, efficiency improvement and high benefit, is suitable for industrial mass production, and has wide application prospects. The urgent demand of the current inhalation auxiliary material lactose for particle size control is solved, and an excellent auxiliary material is provided for the development of inhalation dosage forms in the pharmaceutical industry.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical excipients, and particularly relates to a method for controlling the particle size of lactose for inhalation use. Background Art

[0002] Due to its unique physical and chemical properties, lactose is widely used as a carrier for inhalable drugs. Lactose has the characteristics of being non-toxic, easy to degrade, having low viscosity, and a relatively high glass transition temperature, which makes it easy to flow into powder during spray drying and is very suitable for manufacturing inhalable drugs. In drug preparation, lactose can be used as an excipient, dissolved in water together with active ingredients (such as drugs, nanoparticles), and prepared into inhalable dry powder drugs through spray drying technology.

[0003] Secondly, the application of lactose in dry powder inhalers (DPIs) is particularly prominent. DPI is a drug delivery method that directly inhales drugs in dry powder form into the lungs. As a carrier particle, lactose can effectively improve the atomization performance of drugs in DPI and increase the deposition efficiency of drugs in the lungs. Its particle size directly affects the fluidity, aerosol dispersibility, and lung deposition amount of drugs.

[0004] Specifically, the particle size distribution of lactose affects the formulation characteristics of DPI (dry powder inhaler). When lactose is used as a carrier particle, its particle size is usually relatively large (such as 50 - 500 microns), while drug particles (such as 1 - 5 microns) adhere to the surface of the lactose carrier. This design helps to improve the fluidity and dispersibility of drugs, enabling drugs to reach the lungs more effectively. However, if the particle size of lactose is too large or too small, it may affect the deposition efficiency and therapeutic effect of drugs. Excessively large particle size may cause drugs to deposit in the upper part of the respiratory tract, while too small particle size may cause drugs to be exhaled with breathing and unable to reach the lungs.

[0005] In addition, the particle size of lactose also affects the interaction between drug particles. Appropriate particle size can ensure that drug particles firmly adhere to the lactose carrier, preventing drug agglomeration due to cohesive force during inhalation. At the same time, by controlling the particle size of lactose, the mass ratio between drugs and carriers can also be optimized, thereby improving the separation efficiency and deposition efficiency of drugs.

[0006] Therefore, in the application of inhaled lactose, it is necessary to strictly control the particle size of lactose to ensure the fluidity and dispersibility of drugs, and improve the deposition efficiency and therapeutic effect of drugs. The particle size control technology of lactose is particularly crucial for preparing a lactose for inhalation use, and it has great application prospects. Therefore, there is an urgent need for a method to control the particle size of lactose. Summary of the Invention

[0007] The object of the present invention is to provide a method for controlling the particle size of lactose on the basis of the prior art. First, by means of crystallization, the initial particle size of lactose is controlled and residual proteins, microorganisms, and endotoxins in lactose are removed; then, by means of grinding, the target lactose with different particle size distributions is obtained. The whole control method is simple and easy to operate. By combining crystallization and grinding, it has the advantages of low cost, environmental friendliness, high continuity, cost reduction and efficiency increase, and high benefits, and is suitable for large-scale industrial production.

[0008] The technical solution of the present invention is as follows:

[0009] A method for controlling the particle size of lactose, comprising the following steps:

[0010] (1) Mix the crude lactose with purified water, heat it to 80-100 °C during stirring to completely dissolve it to prepare a lactose solution, then add injection activated carbon, and after heat-preserving stirring and adsorption, perform ultrafiltration using an ultrafiltration filter element;

[0011] (2) Stir and cool the lactose solution after ultrafiltration for crystallization. After crystallization, the lactose solution is centrifuged to obtain wet lactose, and vacuum-dried to obtain dry lactose; wherein, the particle size distribution of the dry lactose is: D10: 20-50 μm, D50: 60-130 μm, D90: 120-240 μm;

[0012] (3) Crush the obtained dry lactose, control the feeding speed, screen aperture and rotation speed to prepare the target lactose for inhalation adjuvant. The particle size distribution of the target lactose is: D10: 1-20 μm, D50: 1-100 μm, D90: 3-220 μm.

[0013] For the present invention, in step (1), the mass ratio of the crude lactose to the purified water is 1:0.5-1.5, which can be but is not limited to 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5. Preferably, the mass ratio of the crude lactose to the purified water is 1:0.5-1.5, and more preferably, the mass ratio of the crude lactose to the purified water is 1:1.0.

[0014] For the present invention, in step (1), heat it to 80-100 °C during stirring. Preferably, heat it to 85-95 °C during stirring, more preferably, heat it to 88-92 °C during stirring, and particularly preferably, heat it to 90 °C during stirring.

[0015] For the present invention, in step (1), the mass of the injection-activated carbon is 0.5‰ - 1.5‰ of the mass of the crude lactose, which can be but is not limited to 0.5‰, 0.6‰, 0.7‰, 0.8‰, 0.9‰, 1.0‰, 1.1‰, 1.2‰, 1.3‰, 1.4‰ or 1.5‰. Preferably, the mass of the injection-activated carbon is 0.8‰ - 1.2‰ of the mass of the crude lactose. More preferably, the mass of the injection-activated carbon is 1.0‰ of the mass of the crude lactose.

[0016] For the present invention, in step (1), the stirring and adsorption time is 10 - 60 minutes, which can be but is not limited to 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes or 60 minutes. Preferably, the stirring and adsorption time is 20 - 40 minutes. More preferably, the stirring and adsorption time is 30 minutes.

[0017] In the present invention, first, the crystallization method is used to control the initial particle size of lactose. The important parameters affecting the initial particle size of lactose mainly include crystallization time, crystallization temperature, cooling rate, and stirring speed. Under the condition that other parameters are the same, shortening the crystallization time can limit the crystal growth stage and obtain a smaller initial particle size. Under the condition that other parameters are the same, lowering the crystallization temperature can increase the supersaturation of the solution (the degree to which the solute concentration in the solution exceeds the equilibrium concentration), promote the rapid formation of crystal nuclei, inhibit crystal growth, and reduce the initial particle size. Under the condition that other parameters are the same, rapid cooling will cause the solution to reach a high supersaturation instantaneously, trigger explosive nucleation, and generate a large number of tiny crystal nuclei. Due to the large number of crystal nuclei, the solute is distributed to more particles, and the growth space of each crystal is limited, resulting in a smaller final initial particle size. Under the condition that other parameters are the same, increasing the stirring speed can increase the mechanical shear force, promote secondary nucleation, inhibit crystal agglomeration, and obtain a smaller initial particle size.

[0018] For the present invention, in step (2), when stirring and cooling for crystallization, the cooling rate is controlled at 1℃ / min - 10℃ / min; preferably, the cooling rate is controlled at 2℃ / min - 5℃ / min.

[0019] For the present invention, in step (2), when stirring and cooling for crystallization, the stirring speed is controlled at 200 rpm - 2000 rpm; preferably, the stirring speed is controlled at 800 rpm - 1500 rpm.

[0020] For the present invention, in step (2), when stirring and cooling for crystallization, the crystallization time is controlled at 1 - 10 hours; preferably, the crystallization time is controlled at 4 - 6 hours.

[0021] For the present invention, in step (2), the crystallization end temperature is 20 - 40℃; preferably, the crystallization end temperature is 25 - 30℃.

[0022] In the present invention, the initial particle size of lactose is first controlled by crystallization. The particle size distribution of the dry lactose product is: D10: 10 - 50 μm, D50: 60 - 140 μm, D90: 110 - 240 μm.

[0023] In a preferred embodiment, the particle size distribution of the dry lactose product is: D10: 20 - 40 μm, D50: 90 - 120 μm, D90: 200 - 230 μm; further preferably, the particle size distribution of the dry lactose product is: D10: 25 - 35 μm, D50: 95 - 105 μm, D90: 210 - 220 μm.

[0024] In another preferred embodiment, the particle size distribution of the dry lactose product is: D10: 10 - 30 μm, D50: 70 - 100 μm, D90: 125 - 155 μm; further preferably, the particle size distribution of the dry lactose product is: D10: 15 - 25 μm, D50: 80 - 90 μm, D90: 135 - 145 μm.

[0025] In the present invention, the initial particle size of lactose is first controlled by crystallization, and then the target particle size of lactose is controlled by crushing. The important parameters affecting the target particle size mainly include the feeding speed, screen aperture, and rotational speed of the grinding and pulverizing machine. The feeding speed is an important factor affecting the particle size after crushing. Under the condition that other parameters are the same, too fast a feeding speed results in too short a residence time of the material in the crushing chamber, and the material cannot be fully broken, thus making the target lactose particle size too large. On the contrary, too slow a feeding speed may cause excessive crushing of lactose, resulting in too fine a particle size. Under the condition that other parameters are the same, the smaller the screen aperture, the finer the discharged particles. Therefore, the target lactose particle size can be reduced by replacing the screen with a smaller aperture. Under the condition that other parameters are the same, the rotational speed is also an important factor affecting the particle size. The higher the rotational speed, the better the crushing effect, and a lower target lactose particle size can be obtained.

[0026] For the present invention, in step (3), the feeding speed is controlled at 5 g / min - 150 g / min; preferably, the feeding speed is controlled at 10 g / min - 100 g / min.

[0027] For the present invention, in step (3), the screen aperture is controlled at 50 mesh - 1500 mesh; preferably, the screen aperture is controlled at 100 mesh - 1250 mesh.

[0028] For the present invention, in step (3), the rotational speed is controlled at 200 rpm - 2500 rpm; preferably, the rotational speed is controlled at 800 rpm - 2000 rpm.

[0029] In the present invention, the initial particle size of lactose is first controlled by crystallization, and then the target particle size of lactose is controlled by grinding. The particle size distribution of the target lactose is as follows: D10: 1 - 20 μm, D50: 1 - 100 μm, D90: 3 - 220 μm.

[0030] In a preferred embodiment, the particle size distribution of the target lactose is: D10: 5 - 15 μm, D50: 50 - 80 μm, D90: 130 - 160 μm; Further preferably, the particle size distribution of the target lactose is: D10: 10 - 13 μm, D50: 60 - 70 μm, D90: 140 - 150 μm.

[0031] In another preferred embodiment, the particle size distribution of the target lactose is: D10: 3 - 12 μm, D50: 40 - 70 μm, D90: 120 - 150 μm; Further preferably, the particle size distribution of the target lactose is: D10: 5 - 8 μm, D50: 50 - 60 μm, D90: 130 - 140 μm.

[0032] In another preferred embodiment, the particle size distribution of the target lactose is: D10: 1 - 7 μm, D50: 30 - 60 μm, D90: 90 - 120 μm; Further preferably, the particle size distribution of the target lactose is: D10: 2 - 4 μm, D50: 40 - 50 μm, D90: 100 - 110 μm.

[0033] In another preferred embodiment, the particle size distribution of the target lactose is: D10: 1 - 5 μm, D50: 1 - 10 μm, D90: 5 - 10 μm; Further preferably, the particle size distribution of the target lactose is: D10: 1 - 3 μm, D50: 3 - 5 μm, D90: 6 - 8 μm.

[0034] In the present invention, the initial particle size of lactose is first controlled by crystallization, meeting the requirements for residual protein (≤0.02%), microorganisms (≤100 cfu / g), and endotoxin (≤5 Eu / g) in lactose. Compared with alcohol-water crystallization, using only water crystallization is cleaner and lower-cost. The combined use of high temperature during dissolution, activated carbon for injection, and ultrafiltration during crystallization has a particularly significant effect on removing residual protein, microorganisms, and endotoxin in lactose. Then, by using the grinding and pulverizing method, lactose for inhalation with different particle size distributions can be prepared, solving the urgent need for particle size control of lactose as an inhalation excipient at present, and providing an excellent excipient for the development of inhalation dosage forms in the pharmaceutical industry.

[0035] The advantages of adopting the technical solution of the present invention are as follows:

[0036] The present invention provides a method for controlling the particle size of lactose. First, by means of crystallization, the initial particle size of lactose is controlled and residual proteins, microorganisms, and endotoxins in lactose are removed. Then, by means of grinding, the target lactose with different particle size distributions is obtained. The whole control method is simple and easy to operate. By combining crystallization and grinding, it has the advantages of low cost, environmental friendliness, high continuity, cost reduction and efficiency increase, and high benefits. It is suitable for large-scale industrial production, solves the urgent need for particle size control of lactose for inhalation excipients at present, and provides an excellent excipient for the development of inhalation dosage forms in the pharmaceutical industry. Description of the Drawings

[0037] Figure 1 is the initial particle size distribution diagram of the dry lactose in Example 1;

[0038] Figure 2 is the particle size distribution diagram of the obtained target lactose in Example 1;

[0039] Figure 3 is the particle size distribution diagram of the obtained target lactose in Example 2;

[0040] Figure 4 is the initial particle size distribution diagram of the dry lactose in Example 3;

[0041] Figure 5 is the particle size distribution diagram of the obtained target lactose in Example 3;

[0042] Figure 6 is the particle size distribution diagram of the obtained target lactose in Example 4. Detailed Embodiments

[0043] According to the following embodiments, the present invention can be better understood. However, those skilled in the art can easily understand that the content described in the embodiments is only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0044] Example 1

[0045] The present invention provides a method for controlling the particle size of lactose, including the following steps:

[0046] (1) Weigh 35 kg of lactose crude product, put it into a 50 L glass reaction kettle, add 35 L of purified water, heat it to 90 °C during stirring to completely dissolve it to prepare a lactose solution, then add 35 g of injection activated carbon, keep stirring and adsorb at 90 °C for 30 minutes, and perform ultrafiltration while it is hot using an ultrafiltration filter element.

[0047] (2) The lactose solution after ultrafiltration is pressure-filtered into a 50L crystallization kettle in the purification workshop, and stirred and cooled for crystallization. The stirring speed is controlled at 800 rpm, the cooling speed is 2°C per minute, the crystallization time is controlled at 6 hours, the final crystallization temperature is 30°C. The lactose solution after crystallization is centrifuged in a centrifuge to obtain 27 kg of wet lactose. It is vacuum-dried at -0.09 Mpa and 35°C for 10 hours to obtain 26.7 kg of dry lactose. The yield is 76.3%. The initial particle size distribution is: D10: 29.12 μm, D50: 97.34 μm, D90: 215.1 μm.

[0048] (3) Put 26.7 kg of dry lactose into the feeding hopper of a grinding and pulverizing machine. Control the feeding speed at 100 g / min, the sieve mesh at 100 meshes, and the pulverizer rotation speed at 800 rpm to prepare the target lactose as an excipient for inhalation. The particle size distribution is: D10: 11.91 μm, D50: 63.85 μm, D90: 145.3 μm. The residual protein (≤0.02%), microorganisms (≤100 cfu / g), and endotoxin (≤5 Eu / g) in the target lactose are detected.

[0049] Example 2

[0050] The present invention provides a method for controlling the particle size of lactose. Among them, the preparation method of dry lactose is the same as that in Example 1, and specifically includes the following steps:

[0051] (1) Weigh 35 kg of crude lactose and put it into a 50L glass reaction kettle. Add 35L of purified water, heat it to 90°C during stirring to completely dissolve it to prepare a lactose solution. Then add 35 g of injection-activated carbon, keep stirring and adsorb at 90°C for 30 minutes, and perform ultrafiltration while it is hot using an ultrafiltration filter element.

[0052] (2) The lactose solution after ultrafiltration is pressure-filtered into a 50L crystallization kettle in the purification workshop, and stirred and cooled for crystallization. The stirring speed is controlled at 800 rpm, the cooling speed is 2°C per minute, the crystallization time is controlled at 6 hours, the final crystallization temperature is 30°C. The lactose solution after crystallization is centrifuged in a centrifuge to obtain 27 kg of wet lactose. It is vacuum-dried at -0.09 Mpa and 35°C for 10 hours to obtain 26.7 kg of dry lactose. The yield is 76.3%. The initial particle size distribution is: D10: 29.12 μm, D50: 97.34 μm, D90: 215.1 μm.

[0053] (3) Charge 26.7 kg of dry lactose into the feed hopper of a grinding and pulverizing machine, control the feed rate at 80 g / min, use a 100-mesh sieve, and set the pulverizer rotation speed at 1000 rpm to obtain the target lactose for inhalation use. The particle size distribution is as follows: D10: 6.767 μm, D50: 56.29 μm, D90: 133.9 μm. After testing, the residual protein (≤0.02%), microorganisms (≤100 cfu / g), and endotoxin (≤5 Eu / g) in the target lactose meet the standards.

[0054] Example 3

[0055] The present invention provides a method for controlling the particle size of lactose, which includes the following steps:

[0056] (1) Weigh 35 kg of crude lactose and charge it into a 50-L glass reaction kettle. Add 35 L of purified water, heat it to 90 °C with stirring to completely dissolve it to prepare a lactose solution. Then add 35 g of injection-grade activated carbon, keep stirring and adsorb at 90 °C for 30 minutes, and perform ultrafiltration while it is hot using an ultrafiltration filter element.

[0057] (2) The lactose solution after ultrafiltration is pressure-filtered into a 50-L crystallization kettle in a purification workshop, stirred and cooled for crystallization. Control the stirring speed at 1500 rpm, the cooling rate at 5 °C / min, the crystallization time at 4 hours, and the end temperature of crystallization at 25 °C. The lactose solution after crystallization is centrifuged in a centrifuge to obtain 27.3 kg of wet lactose, which is vacuum-dried at -0.09 Mpa and 35 °C for 10 hours to obtain 27.0 kg of dry lactose. The yield is 77.1%. The initial particle size distribution is: D10: 20.02 μm, D50: 85.99 μm, D90: 140.6 μm.

[0058] (3) Charge 27.0 kg of dry lactose into the feed hopper of a grinding and pulverizing machine, control the feed rate at 50 g / min, use a 180-mesh sieve, and set the pulverizer rotation speed at 1200 rpm to obtain the target lactose for inhalation use. The particle size distribution is as follows: D10: 3.947 μm, D50: 45.42 μm, D90: 103.4 μm. After testing, the residual protein (≤0.02%), microorganisms (≤100 cfu / g), and endotoxin (≤5 Eu / g) in the target lactose meet the standards.

[0059] Example 4

[0060] The present invention provides a method for controlling the particle size of lactose. The preparation method of dry lactose is the same as that in Example 3, and specifically includes the following steps:

[0061] (1) Weigh 35 kg of crude lactose and put it into a 50 L glass reactor. Add 35 L of purified water and heat it to 90 °C with stirring to completely dissolve it to prepare a lactose solution. Then add 35 g of injection-grade activated carbon and stir and adsorb at 90 °C for 30 minutes. Ultrafilter it while it is hot using an ultrafiltration filter element.

[0062] (2) The lactose solution after ultrafiltration is pressure-filtered into a 50 L crystallization kettle in the purification workshop, and then stirred and cooled for crystallization. Control the stirring speed at 1500 rpm, the cooling rate at 5 °C / minute, the crystallization time at 4 hours, and the final crystallization temperature at 25 °C. The lactose solution after crystallization is centrifuged in a centrifuge to obtain 27.3 kg of wet lactose. Vacuum dry it at -0.09 Mpa and 35 °C for 10 hours to obtain 27.0 kg of dry lactose. The yield is 77.1%, and the initial particle size distribution is: D10: 20.02 μm, D50: 85.99 μm, D90: 140.6 μm.

[0063] (3) Put 27.0 kg of dry lactose into the feed hopper of a grinding and pulverizing machine. Control the feeding speed at 10 g / min, the sieve mesh at 1250 mesh, and the pulverizer rotation speed at 2000 rpm to obtain the target lactose as an excipient for inhalation. The particle size distribution is: D10: 1.115 μm, D50: 3.268 μm, D90: 6.434 μm. After testing, the residual protein (≤0.02%), microorganisms (≤100 cfu / g), and endotoxin (≤5 Eu / g) in the target lactose meet the standards.

[0064] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that it is still possible to modify the technical solutions described in the foregoing embodiments, or to equivalently replace some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for controlling the particle size of lactose, characterized in that, It includes the following steps: (1) Mix the crude lactose with purified water, heat it to 80 - 100°C during stirring to completely dissolve it to prepare a lactose solution, then add injection activated carbon, after heat preservation and stirring adsorption, perform ultrafiltration using an ultrafiltration filter element; (2) Stir and cool the lactose solution after ultrafiltration for crystallization, after crystallization, centrifuge the lactose solution to obtain wet lactose, and vacuum dry it to obtain dry lactose; wherein, the particle size distribution of the dry lactose is: D10: 10 - 50μm, D50: 60 - 140μm, D90: 110 - 240μm; (3) Crush the obtained dry lactose, control the feeding speed, screen aperture and rotation speed to prepare the target lactose as an excipient for inhalation, and the particle size distribution of the target lactose is: D10: 1 - 20μm, D50: 1 - 100μm, D90: 3 - 220μm.

2. The method for controlling the particle size of lactose according to claim 1, wherein In step (1), the mass ratio of the crude lactose to the purified water is 1:0.5 - 1.5, preferably 1:0.8 - 1.2, more preferably 1:1.0; heat it to 85 - 95°C during stirring, preferably 88 - 92°C, more preferably 90°C.

3. The method for controlling the particle size of lactose according to claim 1, wherein In step (1), the mass of the injection activated carbon is 0.5‰ - 1.5‰ of the mass of the crude lactose, preferably 0.8‰ - 1.2‰, more preferably 1.0‰; the stirring adsorption time is 10 - 60 minutes, preferably 20 - 40 minutes, more preferably 30 minutes.

4. The method for controlling the lactose particle size according to claim 1, wherein In step (2), when stirring and cooling for crystallization, the cooling rate is controlled at 1°C / minute - 10°C / minute; preferably, the cooling rate is controlled at 2°C / minute - 5°C / minute.

5. The method for controlling the particle size of lactose according to claim 1, characterized in that, In step (2), when stirring and cooling for crystallization, the stirring speed is controlled at 200rpm - 2000rpm; preferably, the stirring speed is controlled at 800rpm - 1500rpm.

6. The method for controlling the particle size of lactose according to claim 1, wherein In step (2), when stirring and cooling for crystallization, the crystallization time is controlled at 1 - 10 hours; preferably, the crystallization time is controlled at 4 - 6 hours; the crystallization end temperature is 20 - 40°C; preferably, the crystallization end temperature is 25 - 30°C.

7. The method for controlling the lactose particle size according to claim 1, wherein, In step (2), the particle size distribution of the dry lactose is: D10: 20 - 40μm, D50: 90 - 120μm, D90: 200 - 230μm; preferably, the particle size distribution of the dry lactose: D10: 25 - 35μm, D50: 95 - 105μm, D90: 210 - 220μm; or, the particle size distribution of the dry lactose: D10: 10 - 30μm, D50: 70 - 100μm, D90: 125 - 155μm; preferably, the particle size distribution of the dry lactose: D10: 15 - 25μm, D50: 80 - 90μm, D90: 135 - 145μm.

8. The method for controlling the particle size of lactose according to claim 1, characterized in that, In step (3), the feeding speed is controlled at 5g / min - 150g / min; preferably, the feeding speed is controlled at 10g / min - 100g / min.

9. The method for controlling the particle size of lactose according to claim 1, wherein, In step (3), the screen aperture is controlled to be 50 mesh - 1500 mesh; preferably, the screen aperture is controlled to be 100 mesh - 1250 mesh; the rotation speed is controlled to be 200 rpm - 2500 rpm; preferably, the rotation speed is controlled to be 800 rpm - 2000 rpm.

10. The method for controlling the particle size of lactose according to claim 1, wherein, In step (3): The particle size distribution of the target lactose is: D10: 5 - 15 μm, D50: 50 - 80 μm, D90: 130 - 160 μm; preferably, the particle size distribution of the target lactose: D10: 10 - 13 μm, D50: 60 - 70 μm, D90: 140 - 150 μm; The particle size distribution of the target lactose: D10: 3 - 12 μm, D50: 40 - 70 μm, D90: 120 - 150 μm; preferably, the particle size distribution of the target lactose: D10: 5 - 8 μm, D50: 50 - 60 μm, D90: 130 - 140 μm; The particle size distribution of the target lactose: D10: 1 - 7 μm, D50: 30 - 60 μm, D90: 90 - 120 μm; preferably, the particle size distribution of the target lactose: D10: 2 - 4 μm, D50: 40 - 50 μm, D90: 100 - 110 μm; The particle size distribution of the target lactose: D10: 1 - 5 μm, D50: 1 - 10 μm, D90: 5 - 10 μm; preferably, the particle size distribution of the target lactose: D10: 1 - 3 μm, D50: 3 - 5 μm, D90: 6 - 8 μm.

Images