Preparation method of lactose serving as inhalation preparation carrier

Abstract

The invention discloses a preparation method of lactose serving as an inhalation preparation carrier, and belongs to the technical field of pharmaceutical excipients, and the preparation method comprises the following steps: (1) adding superfine lactose seed crystals into ethanol, then dropwise adding a lactose aqueous solution with the mass concentration of 30-60% under the condition of stirring, and continuously stirring for at least 30 minutes after the addition is completed; (2) filtering the solution, and washing a filter cake with ethanol; (3) drying and sieving the filter cake; the lactose prepared by the method is wider in particle size distribution and mainly concentrated in two sections, one section is concentrated in the particle size of fine particles of 1-5 microns, the particle size is close to the particle size of a medicine in an inhalation preparation, and the dispersity of the medicine can be improved; the particle size of the second section is 75-200 microns, the coarse particle can meet the requirement of a third component carrier, and the overall fluidity of lactose is improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical excipients, and particularly relates to a preparation method of lactose as a carrier for inhalation preparations. Background Art

[0002] Inhalation preparations were first used for the treatment of asthma and chronic obstructive pulmonary disease. After years of development, their application scope has gradually expanded to other disease fields, such as pulmonary tuberculosis, diabetes, viral influenza, and pulmonary infections, etc.; meanwhile, the delivery of drugs through the inhalation route has gradually expanded from chemical drugs to biopharmaceuticals (such as peptides and proteins). Due to the advantages of lactose, such as low respiratory irritation and pulmonary adverse reactions, low water content, and low cost, it has become the preferred material for inhalation carriers.

[0003] In order to enable inhaled powders to reach the respiratory tract and even the peripheral tissues of the lungs, their aerodynamic particle size must be in the inhalable range (1 - 5 μm). If the particle size is too large, it is likely to deposit in the oropharynx due to inertial impaction, and if the particle size is too small, it will be exhaled with the airflow. However, due to the too small particle size of inhaled powders, the cohesive forces such as van der Waals force and electrostatic force between particles are relatively strong, resulting in poor fluidity of the powders, which is not conducive to the filling of powders or ensuring the content uniformity of divided doses; in severe cases, it may even make it difficult for the powders to redisperse into particles smaller than 5 μm after ejection, which is not conducive to transporting drugs to the lungs. To optimize the fluidity and dispersibility of powders in inhalation preparations, it is often necessary to introduce coarse-grained lactose as a third component, but this process improvement also brings additional mixing processes and potential problems of uneven mixing.

[0004] Currently, lactose raw materials used as carriers for inhalation preparations are usually prepared by means such as spray drying, freeze drying, or mechanical grinding. These preparation methods are costly and have complex operating methods. For example, when preparing lactose by spray drying, due to the relatively high temperature and pressure during the drying process, the lactose particles will be relatively brittle, which is not conducive to grinding and mixing; the spray process parameters are fixed, and only lactose with a relatively narrow particle size distribution can be obtained, limiting the application effect of inhalation preparations.

[0005] Chinese Patent CN117018207A discloses a carrier particle for an inhalable powder aerosol and an inhalable powder aerosol containing the carrier particle, and specifically discloses that: the carrier is lactose, including Lactose I, Lactose II, and Lactose III. Based on the total weight of the carrier particle being 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%; among them, 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: A) First, Lactose II and Lactose III are high-shear mixed in a mixing device, then Lactose I is added, and then high-shear mixing is carried out to obtain the mixed lactose; B) The mixed lactose obtained in step A) is exposed to an environment of 30°C - 70°C and RH45% - RH85% for more than 12 hours to obtain the carrier particle. In this patent, it is obtained by shear mixing lactose with different particle sizes and then exposing it to an environment of 30°C - 70°C and RH45% - RH85% for more than 12 hours. This method has cumbersome steps, complex operations, and high production costs. Summary of the Invention

[0006] To solve the above technical problems, the present invention provides a preparation method for lactose as a carrier for an inhalation preparation. The lactose produced by this method has high purity and a wider particle size distribution. There are both fine particles and coarse particles at the same time. The presence of the coarse particles endows it with better fluidity, and there is no need to additionally introduce a third component of coarse particle lactose during use.

[0007] The technical solution adopted by the present invention is as follows:

[0008] A preparation method for lactose as a carrier for an inhalation preparation, the preparation method comprising the following steps:

[0009] (1) Add ultrafine lactose seeds to ethanol, and then, under stirring, dropwise add a lactose aqueous solution with a mass concentration of 30% - 60%, and continue stirring for at least 30 minutes after the addition is completed;

[0010] (2) Filter the solution, and wash the filter cake with ethanol;

[0011] (3) Dry the filter cake and sieve it.

[0012] In step (1), the mass ratio of lactose to ethanol is 1:10 - 50.

[0013] In step (1), the mass ratio of the ultrafine lactose seeds to lactose is 1:50 - 200.

[0014] In step (1), the average particle size of the ultrafine lactose seeds is less than 10 microns.

[0015] In step (1), the mass fraction of the ethanol is 50% to 100%.

[0016] In step (2), the filter cake is washed with ethanol having a mass fraction of 85 to 95%.

[0017] In step (2), the number of times of washing with ethanol is at least two.

[0018] In step (3), the sieving is through a 60-mesh sieve.

[0019] In the lactose used as the carrier of the inhalation preparation, the proportion of fine particles with a size of 1 to 5 μm is 15 to 40%; the proportion of coarse particles with a size of 75 to 200 μm is 7 to 30%.

[0020] The preparation method of lactose provided by the present invention as a carrier for inhalation preparations is to add a 30% to 60% aqueous lactose solution to a poor ethanol solvent containing a small amount of ultrafine lactose seeds, and only one step is used to prepare lactose with a wider particle size distribution, which is mainly concentrated in two sections. One section is concentrated in fine particles with a size of 1 to 5 μm, which is similar to the particle size of the drug in the inhalation preparation, improving the dispersibility of the drug; the other section is concentrated in coarse particles with a size of 75 to 200 μm, which can meet the requirements of the third component carrier and improve the overall fluidity of lactose; by controlling conditions such as the solid-liquid ratio, the ratio of fine and coarse lactose particles can be controlled to meet different needs. And the lactose prepared by this method has high purity.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The preparation method of lactose provided by the present invention as a carrier for inhalation preparations has simple production conditions, requires less equipment, and is easy to control in the production process.

[0023] The lactose produced by the present invention has high purity and a wider particle size distribution. The presence of coarse particles endows it with better fluidity, and there is no need to additionally introduce coarse particle lactose as the third component. Compared with the inhalation lactose prepared by the spray drying method, the mixing step of fine and coarse particle lactose is omitted, greatly avoiding the risk of uneven mixing and stratification due to large differences in particle fineness, and improving the application effect of the inhalation preparation. Detailed implementation mode

[0024] The present invention will be described in detail below with reference to the embodiments.

[0025] Example 1

[0026] A preparation method of lactose as a carrier for inhalation preparations is as follows:

[0027] (1) Take 100 parts of ordinary lactose and disperse it in purified water, stir it at a constant temperature of 70 °C for 30 min to prepare an aqueous lactose solution with a mass concentration of 30%, for later use;

[0028] (2) Take 2000 parts of ethanol with a mass fraction of 95%, and add 2 parts of ultrafine lactose seeds with an average particle size of less than 10 microns. While dripping and starting stirring, slowly drip the lactose aqueous solution into the ethanol with a peristaltic pump. Lactose slowly precipitates in the ethanol. After dripping, continue stirring for 30 min;

[0029] (3) Filter the ethanol solution containing lactose particles. Place the obtained filter cake in ethanol with a mass fraction of 95% according to a solid-liquid ratio of 1:10 and stir and wash for 15 min, then filter. Repeat this step twice;

[0030] (4) Put the obtained filter cake into an oven for drying. After drying, the material does not need to be crushed and is directly passed through a 60-mesh sieve. The material under the sieve is the lactose finished product.

[0031] Example 2

[0032] A preparation method of lactose as a carrier for inhalation preparations is as follows:

[0033] (1) Take 100 parts of ordinary lactose and disperse it in purified water. Stir at a constant temperature of 70 °C for 30 min to prepare a lactose aqueous solution with a mass concentration of 60%, for later use;

[0034] (2) Take 2000 parts of ethanol with a mass fraction of 95%, and add 2 parts of ultrafine lactose seeds with an average particle size of less than 10 microns. While dripping and starting stirring, slowly drip the lactose aqueous solution into the ethanol with a peristaltic pump. Lactose slowly precipitates in the ethanol. After dripping, continue stirring for 30 min;

[0035] (3) Filter the ethanol solution containing lactose particles. Place the obtained filter cake in ethanol with a mass fraction of 95% according to a solid-liquid ratio of 1:10 and stir and wash for 15 min, then filter. Repeat this step twice;

[0036] (4) Put the obtained filter cake into an oven for drying. After drying, the material does not need to be crushed and is directly passed through a 60-mesh sieve. The material under the sieve is the lactose finished product.

[0037] Example 3

[0038] A preparation method of lactose as a carrier for inhalation preparations is as follows:

[0039] (1) Take 100 parts of ordinary lactose and disperse it in purified water. Stir at a constant temperature of 70 °C for 30 min to prepare a lactose aqueous solution with a mass concentration of 40%, for later use;

[0040] (2) Take 1000 parts of ethanol with a mass fraction of 95%, and add 2 parts of ultrafine lactose seeds with an average particle size of less than 10 microns. While dripping and starting stirring, slowly drip the lactose aqueous solution into the ethanol with a peristaltic pump. Lactose slowly precipitates in the ethanol. After dripping, continue stirring for 30 min;

[0041] (3) Filter the ethanol solution containing lactose particles, place the obtained filter cake in 95% ethanol according to a solid-liquid ratio of 1:10, stir and wash for 15 min, and then filter; repeat this step twice.

[0042] (4) Put the obtained filter cake into an oven for drying; after drying, the material does not need to be crushed and is directly passed through a 60-mesh sieve, and the material passing through the sieve is the lactose finished product.

[0043] Example 4

[0044] A preparation method of lactose as a carrier for inhalation preparations, the steps are as follows:

[0045] (1) Take 100 parts of ordinary lactose and disperse it in purified water, stir at a constant temperature of 70 °C for 30 min to prepare a lactose aqueous solution with a mass concentration of 40%, for later use.

[0046] (2) Take 2000 parts of 95% ethanol, add 2 parts of ultrafine lactose seeds with an average particle size of less than 10 microns; while dripping and starting stirring, slowly drip the lactose aqueous solution into the ethanol with a peristaltic pump. Lactose slowly precipitates in the ethanol. After dripping, continue to stir for 30 min.

[0047] (3) Filter the ethanol solution containing lactose particles, place the obtained filter cake in 95% ethanol according to a solid-liquid ratio of 1:10, stir and wash for 15 min, and then filter; repeat this step twice.

[0048] (4) Put the obtained filter cake into an oven for drying; after drying, the material does not need to be crushed and is directly passed through a 60-mesh sieve, and the material passing through the sieve is the lactose finished product.

[0049] Example 5

[0050] A preparation method of lactose as a carrier for inhalation preparations, the steps are as follows:

[0051] (1) Take 100 parts of ordinary lactose and disperse it in purified water, stir at a constant temperature of 70 °C for 30 min to prepare a lactose aqueous solution with a mass concentration of 40%, for later use.

[0052] (2) Take 3000 parts of 95% ethanol, add 2 parts of ultrafine lactose seeds with an average particle size of less than 10 microns; while dripping and starting stirring, slowly drip the lactose aqueous solution into the ethanol with a peristaltic pump. Lactose slowly precipitates in the ethanol. After dripping, continue to stir for 30 min.

[0053] (3) Filter the ethanol solution containing lactose particles, place the obtained filter cake in 95% ethanol according to a solid-liquid ratio of 1:10, stir and wash for 15 min, and then filter; repeat this step twice.

[0054] (4) Place the obtained filter cake in an oven for drying; after drying, the material does not need to be crushed and is directly passed through a 60-mesh sieve, and the product of lactose is obtained under the sieve.

[0055] Comparative Example 1

[0056] Change the mass concentration of the lactose aqueous solution to 10%, and prepare the lactose product in the same manner as in Example 3 for other operations.

[0057] The lactose prepared in Examples 1-5 and Comparative Example 1 and the commercially available crystalline lactose were used to measure the particle size distribution, fineness and absorbance of lactose with a Dandong Baite laser particle size distribution analyzer, an air jet sieve and an ultraviolet spectrophotometer. The results are shown in Table 1.

[0058] Table 1 Summary of sample detection data results

[0059]

[0060]

[0061] Note: Diameter distance = (D90 - D10) / D50; measures the degree of deviation of the particle distribution from the median particle size; the larger the value, the wider the distribution range of the particle size. The proportion below 2500 mesh is used to evaluate the proportion of fine particles in the range of 1-5um, and the proportion above 200 mesh is used to evaluate the proportion of coarse particles in the range of 75-200um.

[0062] As can be seen from Table 1, compared with the commercially available crystalline lactose, the lactose prepared according to Examples 1-5 of the present invention shows lower absorbance, its particle size is generally smaller, the distribution range is wider, it not only contains sufficient fine particles, but also contains a certain proportion of coarse particles, that is, a two-stage particle size distribution is achieved. During the process of dispersing and recrystallizing the lactose aqueous solution in ethanol, the impurity content is effectively reduced. Since impurities are usually the main cause of light scattering and absorption, the absorbance of the lactose treated by the method of the present invention at the detection wavelength is significantly reduced. In addition, by adjusting parameters such as the mass fraction of the lactose aqueous solution and the amount of ethanol used, the rate of lactose aggregation nuclei can be controlled, and the rate of lactose aggregation nuclei and the deposition rate of lactose molecules on the crystal surface can be controlled, thereby effectively regulating the proportion of fine and coarse particles, particle size and distribution of lactose.

[0063] As can be seen from Table 1, compared with Example 3, in Comparative Example 1, when using a lactose aqueous solution with a mass fraction of 10%, the particle size of the obtained lactose product is smaller than that of the lactose product in Example 3, and the particle size distribution is narrower, and the fineness proportion above 200 mesh is 0.00%, indicating that there are no coarse particles in the lactose prepared by this scheme.

[0064] The detailed description of the preparation method of lactose as a carrier for inhalation preparations with reference to the above embodiments is illustrative rather than restrictive. Several embodiments can be enumerated within the defined scope. Therefore, changes and modifications without departing from the general concept of the present invention shall fall within the protection scope of the present invention.

Claims

1. A preparation method of lactose as a carrier for an inhalation preparation, characterized in that, The preparation method comprises the following steps: (1) Add ultrafine lactose seeds to ethanol, and then, with stirring, dropwise add an aqueous lactose solution with a mass concentration of 30% to 60%. After the addition is completed, continue stirring for at least 30 min; (2) Filter the solution and wash the filter cake with ethanol; (3) Dry the filter cake and sieve it.

2. The preparation method of lactose as a carrier for inhalation preparations according to claim 1, characterized in that, In step (1), the mass ratio of lactose to ethanol is 1:10 to 40.

3. The preparation method of lactose as a carrier for inhalation preparations according to claim 1, characterized in that, In step (1), the mass ratio of the ultrafine lactose seeds to lactose is 1:50 to 200.

4. The preparation method of lactose as a carrier for inhalation preparations according to claim 1, characterized in that, In step (1), the average particle size of the ultrafine lactose seeds is less than 10 μm.

5. The preparation method of lactose as a carrier for an inhalation preparation according to claim 1, characterized in that, In step (1), the mass fraction of the ethanol is 50% to 100%.

6. The preparation method of lactose as a carrier for inhalation preparations according to claim 1, characterized in that, In step (2), wash the filter cake with ethanol with a mass fraction of 85% to 95%.

7. The preparation method of lactose as a carrier for an inhalation preparation according to claim 1, characterized in that, In step (2), the number of times of washing with ethanol is at least two.

8. The preparation method of lactose as a carrier for inhalation preparations according to claim 1, characterized in that, In step (3), the sieving is through a 60-mesh sieve.

9. The preparation method of lactose as a carrier for inhalation preparations according to any one of claims 1-8, characterized in that, In the lactose used as a carrier for inhalation preparations, the proportion of fine particles with a size of 1 to 5 μm is 15% to 40%; the proportion of coarse particles with a size of 75 to 200 μm is 7% to 30%.

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