A kind of beclomethasone dipropionate suspension for inhalation and preparation method thereof

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and specifically discloses a beclomethasone dipropionate suspension for inhalation and a preparation method thereof. The present invention uses polyethylene glycol hyaluronic acid as a surfactant, polysorbate 80 (II) as a wetting agent, and colloidal microcrystalline cellulose as a suspending agent, first prepares an auxiliary material solution containing part of the surfactant, the wetting agent and the suspending agent, and a drug solution of beclomethasone dipropionate and the surfactant, and then mixes the drug solution with the auxiliary material solution and homogenizes under high pressure to prepare the beclomethasone dipropionate suspension for inhalation. The prepared beclomethasone dipropionate suspension has excellent storage stability and effective lung deposition rate, effectively solves the potential harm to respiratory tissue caused by the use of a large amount of Tween 20 and Span-type surfactants in the original research, can achieve a good replacement for the original research product, and has a simple preparation process, good repeatability, and is easy to achieve industrialized large-scale production, and has a high value of promotion and application.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a beclomethasone dipropionate suspension for inhalation and a preparation method thereof. Background Art

[0002] In today's society, the incidence of respiratory diseases remains high, and asthma, chronic obstructive pulmonary disease (COPD) and other diseases have become a problem that plagues the health of many patients. According to statistics from the World Health Organization, hundreds of millions of people in the world suffer from asthma, and the incidence rate is increasing year by year. COPD is affected by factors such as aging, and the patient population is growing. These diseases not only seriously affect the patient's daily activities and reduce the quality of life, but may also endanger life during acute attacks. Although traditional treatments such as oral glucocorticoids can relieve symptoms to a certain extent, they have large systemic adverse reactions. Long-term use can cause many problems such as osteoporosis, increased blood sugar, and decreased immunity, which brings additional health burdens to patients. Compared with oral administration, inhalation administration allows the drug to directly reach the site of action-the respiratory tract and lungs, greatly increasing the local concentration of the drug and quickly exerting its efficacy. At the same time, since the drug mainly takes effect locally, the amount of drug entering the blood circulation is relatively small, which significantly reduces the risk of systemic adverse reactions and provides a safer and more effective treatment option for patients who need long-term medication to control their condition.

[0003] Beclomethasone dipropionate is a synthetic, potent adrenal cortical hormone drug with excellent anti-inflammatory, anti-allergic and antipruritic effects. It can effectively inhibit bronchial exudates, eliminate bronchial mucosal swelling, and relieve bronchospasm. Beclomethasone dipropionate can be used as an aerosol inhalation preparation with obvious advantages and is widely used in the field of inhalation therapy.

[0004] However, there are still some technical problems that need to be solved in the inhaled beclomethasone dipropionate suspension on the market. On the one hand, in terms of the stability of the suspension, the beclomethasone dipropionate drug particles are prone to agglomeration and sedimentation, resulting in the drug not being evenly dispersed during the atomization process, affecting the accuracy of the drug dosage inhaled by the patient each time, and thus affecting the treatment effect. On the other hand, the uneven particle size of some existing preparations leads to poor effective lung deposition rate. If the particle size of the suspension is too large, it is easy to be deposited in the upper respiratory tract due to inertial collision during respiratory transmission, and it cannot penetrate into the lungs to play a role, causing a large amount of drugs to be unable to reach the target site; on the contrary, particles with too small a particle size will be discharged from the body with the exhaled airflow, which also reduces the lung deposition rate. Therefore, the development of a beclomethasone dipropionate suspension for inhalation with high stability and high effective lung deposition rate has extremely important practical significance and urgent market demand. Summary of the invention

[0005] Aiming at the problems of low effective lung deposition rate and poor storage stability of existing beclomethasone dipropionate suspension for inhalation, the present invention provides a beclomethasone dipropionate suspension for inhalation and a preparation method thereof.

[0006] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0007] A beclomethasone dipropionate suspension for inhalation comprises beclomethasone dipropionate, polyethylene glycol hyaluronic acid, polysorbate 80 (II) and colloidal microcrystalline cellulose.

[0008] Compared with the prior art, the beclomethasone dipropionate suspension for inhalation provided by the present invention selects polyethylene glycol hyaluronic acid as a surfactant to increase the solubility of beclomethasone dipropionate in water. At the same time, the polyethylene glycol hyaluronic acid can be adsorbed on the surface of beclomethasone dipropionate particles, and its long chain structure can provide steric hindrance to prevent the drug particles from agglomerating due to mutual collision, thereby helping to form a suspension system with more uniform particle size and better stability; polysorbate 80 (II) is selected as a wetting agent to improve the affinity of beclomethasone dipropionate with water, and increase the affinity of the suspension particles with the human respiratory mucosa, thereby improving the effective lung deposition rate of the suspension; colloidal microcrystalline cellulose is selected as a suspending agent It can effectively improve the aggregation of suspension particles and reduce the number of redispersion flipping times of the suspension, improve the uniform dispersion of the suspension during the atomization process, ensure the accuracy of the drug dosage inhaled by the patient each time, and avoid the occurrence of problems such as uneven drug distribution causing the patient to inhale too many drug particles at one time and produce adverse reactions, or insufficient inhaled drug volume and fail to achieve the expected therapeutic effect, which is conducive to ensuring a good therapeutic effect. In addition, colloidal microcrystalline cellulose can stabilize the structure of the droplets of the suspension after atomization, prevent the droplets from breaking or deforming due to evaporation or collision during flight, ensure that the droplets can reach the lungs intact, and effectively deposit the drug in the lung tissue, thereby improving the effective deposition rate of the lungs.

[0009] The beclomethasone dipropionate suspension of the present invention is synergistically constructed with polyethylene glycol hyaluronic acid, polysorbate 80 (II) and colloidal microcrystalline cellulose, and has excellent physical stability and chemical stability. The suspension can also always maintain a stable appearance and uniform drug distribution during long-term storage and transportation, and when performing a redispersion operation before each use, only a simple shake is required, and the drug particles can quickly restore a uniform suspension state, ensuring that the drug dose inhaled by the patient each time is accurate and consistent, greatly improving the reliability of the treatment effect; in addition, through the synergy of polyethylene glycol hyaluronic acid and colloidal microcrystalline cellulose, the droplet size can also be maintained within a range that is conducive to lung deposition, and after the drug droplets reach the lungs, polysorbate 80 (II) can help the drug penetrate the mucus layer covering the surface of the respiratory tract of the lungs, thereby improving the effective deposition and absorption of the drug in the lungs, and improving the effective deposition rate of the lungs.

[0010] Furthermore, the beclomethasone dipropionate suspension for inhalation also includes an isotonicity regulator, a pH regulator and water for injection beclomethasone dipropionate suspension for inhalation.

[0011] Furthermore, the beclomethasone dipropionate suspension for inhalation comprises the following components in parts by mass: 1 part of beclomethasone dipropionate, 0.5 to 1.5 parts of polyethylene glycol hyaluronic acid, 0.05 to 0.3 parts of polysorbate 80 (II), 0.3 to 0.7 parts of colloidal microcrystalline cellulose, 19 to 23 parts of isotonicity regulator, 0.01 to 0.1 parts of pH regulator and 2490 to 2510 parts of water for injection.

[0012] Furthermore, the beclomethasone dipropionate suspension for inhalation comprises the following components in parts by mass: 1 part of beclomethasone dipropionate, 1 part of polyethylene glycol hyaluronic acid, 0.2 parts of polysorbate 80 (II), 0.5 parts of colloidal microcrystalline cellulose, 22.5 parts of isotonicity regulator, 0.05 parts of pH regulator and 2500 parts of water for injection.

[0013] Furthermore, the molecular weight of hyaluronic acid in the polyethylene glycol hyaluronic acid is 5000Da to 12000Da, and the molecular weight of polyethylene glycol is 2000Da to 4000Da.

[0014] The preferred polyethylene glycol hyaluronic acid can improve the uniformity of particle size and reduce particle agglomeration, thereby reducing the number of redispersion turnovers of the suspension.

[0015] Furthermore, the colloidal microcrystalline cellulose is selected from

[0016] As a suspending agent, colloidal microcrystalline cellulose contains abundant hydroxyl groups that can form hydrogen bonds with drug particles to form a stable three-dimensional network structure in the suspension, effectively slowing down the sedimentation rate of drug particles and ensuring that the drug can still be evenly dispersed after standing for a long time. At the same time, it can also prevent droplets from breaking or deforming due to evaporation or collision during flight, ensuring that droplets can reach the lungs intact and effectively deposit the drug in the lung tissue, thereby improving the effective deposition rate in the lungs.

[0017] Exemplarily, the isotonicity adjusting agent is sodium chloride.

[0018] Exemplarily, the pH adjuster is sodium hydroxide.

[0019] It should be noted that the present invention may also use other isotonicity adjusting agents and pH adjusting agents that are conventionally acceptable in the pharmaceutical field, and the present invention does not make any special limitations.

[0020] The present invention also provides a method for preparing the beclomethasone dipropionate suspension for inhalation, comprising the following steps:

[0021] S1, dissolving 99% to 99.5% of the prescribed amount of polyethylene glycol hyaluronic acid in the first part of the injection water to obtain a polyethylene glycol hyaluronic acid solution;

[0022] Dissolving the prescribed amount of polysorbate 80(II) in the second portion of water for injection to obtain a polysorbate 80(II) solution;

[0023] dissolving the prescribed amount of colloidal microcrystalline cellulose in the third portion of water for injection to obtain a colloidal microcrystalline cellulose solution;

[0024] S2, mixing the polyethylene glycol hyaluronic acid solution, polysorbate 80 (II) solution and colloidal microcrystalline cellulose solution uniformly, adding a prescribed amount of an isotonicity adjusting agent, mixing uniformly, then adding a pH adjusting agent to adjust the pH to 4-6, filtering and sterilizing, and obtaining an auxiliary material solution;

[0025] S3, dissolving the remaining polyethylene glycol hyaluronic acid in the remaining water for injection, adding the prescribed amount of beclomethasone dipropionate, mixing evenly, sterilizing, adding the auxiliary material solution, mixing evenly, high pressure homogenizing, filling, and obtaining the beclomethasone dipropionate suspension for inhalation.

[0026] The preparation method of the beclomethasone dipropionate suspension for inhalation provided by the present invention comprises the following steps: firstly, a part of the surfactant, a prescribed amount of a wetting agent, a suspending agent and other auxiliary materials are uniformly mixed to form a relatively stable and uniform environment, thereby providing a more stable basis for the subsequent suspension of drug particles; and then, the remaining surfactant is uniformly mixed with beclomethasone acrylate, so that the surface of the beclomethasone dipropionate particles can be fully covered by the surfactant, thereby preventing the mutual collision and agglomeration between the drug particles, and further adjusting the surface properties of the drug particles, thereby increasing the affinity of the drug particles with water for injection, thereby making the system more conducive to the dispersion of the drug particles, thereby making the particle size of the drug particles more uniform, and being conducive to maintaining a stable dispersion state during subsequent storage and use.

[0027] Furthermore, the temperature of the water for injection used in the preparation process is 40°C to 60°C.

[0028] It should be noted that the beclomethasone dipropionate raw material used in the present invention is micronized beclomethasone dipropionate with a particle size of 1 to 4 μm.

[0029] Furthermore, in S1, the first part of the water for injection is 75% to 85% of the prescribed amount; the second part of the water for injection is 3% to 5% of the prescribed amount; and the third part 1 of the water for injection is 3% to 5% of the prescribed amount.

[0030] Furthermore, in S3, the sterilization temperature is 121° C., the sterilization time is 10 min to 15 min, and the pore size of the filter membrane used for filtration is 0.22 μm.

[0031] Furthermore, in S3, the pressure of the high-pressure homogenization is 20 MPa to 50 MPa, and the number of homogenization times is 20 to 50 times.

[0032] Exemplarily, in S3, a bottle blowing, filling and sealing integrated machine is used for filling and sealing.

[0033] Exemplarily, in S3, the volume of each single-dose package is 2.1 to 2.3 mL.

[0034] Furthermore, the particle size of the beclomethasone dipropionate suspension for inhalation is 1 μm to 4 μm.

[0035] The invention uses polyethylene glycol hyaluronic acid as a surfactant, polysorbate 80 (II) as a wetting agent, and colloidal microcrystalline cellulose as a suspending agent, first prepares an auxiliary material solution containing part of the surfactant, the wetting agent and the suspending agent, and a drug solution of beclomethasone dipropionate and the surfactant, and then mixes the drug solution with the auxiliary material solution and homogenizes under high pressure to prepare a beclomethasone dipropionate suspension for inhalation. The prepared beclomethasone dipropionate suspension has excellent storage stability and effective lung deposition rate, effectively solves the potential harm to respiratory tissue caused by the use of a large amount of Tween 20 and Span-type surfactants in the original research, can achieve a good replacement for the original research product, and has a simple preparation process, good repeatability, easy to achieve industrial mass production, and has a high value of promotion and application. DETAILED DESCRIPTION

[0036] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0037] In order to better illustrate the present invention, further examples are given below.

[0038] The beclomethasone dipropionate raw material used in the following examples is micronized beclomethasone dipropionate with a particle size of 1 to 4 μm. The molecular weight of hyaluronic acid in polyethylene glycol hyaluronic acid is 8000 to 9000 Da, and the molecular weight of polyethylene glycol is 2000 to 2500 Da.

[0039] Example 1

[0040] This embodiment provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), and the prescription for preparing 110,000 suspension preparations is shown in the following table:

[0041]

[0042] The preparation method of the above-mentioned beclomethasone dipropionate suspension for inhalation is as follows:

[0043] S1, adding 99.2% of the prescribed amount of polyethylene glycol hyaluronic acid into 176L of water for injection (50°C) to dissolve and obtain a surfactant solution;

[0044] Take the prescribed amount of polysorbate-80 (II) and add it to 10L of water for injection (50°C) to dissolve it to obtain a wetting agent solution;

[0045] Take the prescribed amount Add into 10L of water for injection (50℃), dissolve to obtain suspension solution;

[0046] S2, adding the surfactant solution, wetting agent solution and suspending agent solution into a liquid preparation tank, adding a prescribed amount of NaCl, stirring magnetically to dissolve, adjusting the water temperature to 50° C., adding a prescribed amount of sodium hydroxide, and obtaining an auxiliary material solution;

[0047] S3, adding the remaining polyethylene glycol hyaluronic acid to the remaining water for injection (50° C.), stirring to dissolve, adding the prescribed amount of beclomethasone dipropionate, mixing evenly, sterilizing at 121° C. for 10 min, and cooling to room temperature to obtain a drug suspension;

[0048] S4, after filtering the auxiliary material solution through a filter membrane with a pore size of 0.22 μm, add it to the liquid preparation tank, then add the drug suspension, stir evenly, use a high-pressure homogenizer to homogenize 25 times at 40 MPa, fill the obtained suspension through a plastic bottle blowing, filling and sealing integrated machine, seal it, and obtain beclomethasone dipropionate suspension for inhalation.

[0049] Example 2

[0050] This embodiment provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), and the prescription for preparing 110,000 suspension preparations is shown in the following table:

[0051]

[0052] The preparation method of the above-mentioned beclomethasone dipropionate suspension for inhalation is as follows:

[0053] S1, adding 99.0% of the prescribed amount of polyethylene glycol hyaluronic acid into 165 L of water for injection (40° C.), dissolving to obtain a surfactant solution;

[0054] Take the prescribed amount of polysorbate-80 (II) and add it to 10L of water for injection (40°C) to dissolve it to obtain a wetting agent solution;

[0055] Take the prescribed amount Add into 10L of water for injection (40℃), dissolve to obtain suspension solution;

[0056] S2, adding the surfactant solution, wetting agent solution and suspending agent solution into a liquid preparation tank, adding a prescribed amount of NaCl, stirring magnetically to dissolve, adjusting the water temperature to 40° C., adding a prescribed amount of sodium hydroxide, and obtaining an auxiliary material solution;

[0057] S3, adding the remaining polyethylene glycol hyaluronic acid to the remaining water for injection (40° C.), stirring to dissolve, adding the prescribed amount of beclomethasone dipropionate, mixing evenly, sterilizing at 121° C. for 15 min, and cooling to room temperature to obtain a drug suspension;

[0058] S4, after filtering the auxiliary material solution through a filter membrane with a pore size of 0.22 μm, add it to the liquid preparation tank, then add the drug suspension, stir evenly, use a high-pressure homogenizer to homogenize 20 times at 50 MPa, fill the obtained suspension through a plastic bottle blowing, filling and sealing integrated machine, seal it, and obtain beclomethasone dipropionate suspension for inhalation.

[0059] Example 3

[0060] This embodiment provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), and the prescription for preparing 110,000 suspension preparations is shown in the following table:

[0061]

[0062] The preparation method of the above-mentioned beclomethasone dipropionate suspension for inhalation is as follows:

[0063] S1, adding 99.5% of the prescribed amount of polyethylene glycol hyaluronic acid into 170 L of water for injection (40° C.), dissolving to obtain a surfactant solution;

[0064] Take the prescribed amount of polysorbate-80 (II) and add it to 10L of water for injection (40°C) to dissolve it to obtain a wetting agent solution;

[0065] Take the prescribed amount Add into 10L of water for injection (40℃), dissolve to obtain suspension solution;

[0066] S2, adding the surfactant solution, wetting agent solution and suspending agent solution into a liquid preparation tank, adding a prescribed amount of NaCl, stirring magnetically to dissolve, adjusting the water temperature to 40° C., adding a prescribed amount of sodium hydroxide, and obtaining an auxiliary material solution;

[0067] S3, adding the remaining polyethylene glycol hyaluronic acid to the remaining water for injection (40-60° C.), stirring to dissolve, adding the prescribed amount of beclomethasone dipropionate, mixing evenly, sterilizing at 121° C. for 12 min, and cooling to room temperature to obtain a drug suspension;

[0068] S4, after filtering the auxiliary material solution through a filter membrane with a pore size of 0.22 μm, add it to the liquid preparation tank, then add the drug suspension, stir evenly, use a high-pressure homogenizer to homogenize 20 times at 30 MPa, fill the obtained suspension through a plastic bottle blowing, filling and sealing integrated machine, seal it, and obtain beclomethasone dipropionate suspension for inhalation.

[0069] Example 4

[0070] This embodiment provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), and the prescription for preparing 55,000 suspension preparations is shown in the following table:

[0071]

[0072] The preparation method of the above-mentioned beclomethasone dipropionate suspension for inhalation is as follows:

[0073] S1, adding 99.3% of the prescribed amount of polyethylene glycol hyaluronic acid into 93L of water for injection (45°C), dissolving to obtain a surfactant solution;

[0074] Take the prescribed amount of polysorbate-80 (II) and add it to 5L of water for injection (45°C) and dissolve it to obtain a wetting agent solution;

[0075] Take the prescribed amount Add to 5L of water for injection (45°C) and dissolve to obtain a suspending agent solution;

[0076] S2, adding the surfactant solution, wetting agent solution and suspending agent solution into a liquid preparation tank, adding a prescribed amount of NaCl, stirring magnetically to dissolve, adjusting the water temperature to 45° C., adding a prescribed amount of sodium hydroxide, and obtaining an auxiliary material solution;

[0077] S3, adding the remaining polyethylene glycol hyaluronic acid to the remaining water for injection (45° C.), stirring to dissolve, adding the prescribed amount of beclomethasone dipropionate, mixing evenly, sterilizing at 121° C. for 10 min, and cooling to room temperature to obtain a drug suspension;

[0078] S4, after filtering the auxiliary material solution through a filter membrane with a pore size of 0.22 μm, add it to the liquid preparation tank, then add the drug suspension, stir evenly, use a high-pressure homogenizer to homogenize 25 times at 40 MPa, fill the obtained suspension through a plastic bottle blowing, filling and sealing integrated machine, seal it, and obtain beclomethasone dipropionate suspension for inhalation.

[0079] After testing, the particle size of the beclomethasone dipropionate suspension for inhalation prepared in Examples 1 to 4 was 1 to 4 μm.

[0080] Example 5

[0081] This embodiment provides a beclomethasone dipropionate suspension for inhalation, and its prescription is exactly the same as that of Example 1, except that the surfactant and beclomethasone dipropionate are not mixed in advance in the preparation method. The specific preparation method is as follows:

[0082] S1, taking a prescribed amount of polyethylene glycol hyaluronic acid, adding it into 176L of water for injection (50°C), dissolving it to obtain a surfactant solution;

[0083] Take the prescribed amount of polysorbate-80 (II) and add it to 10L of water for injection (50°C) to dissolve it to obtain a wetting agent solution;

[0084] Take the prescribed amount Add into 10L of water for injection (50℃), dissolve to obtain suspension solution;

[0085] S2, adding the surfactant solution, wetting agent solution and suspending agent solution into a liquid preparation tank, adding a prescribed amount of NaCl, stirring magnetically to dissolve, adjusting the water temperature to 50° C., adding a prescribed amount of sodium hydroxide, and obtaining an auxiliary material solution;

[0086] S3, adding the prescribed amount of beclomethasone dipropionate to the remaining water for injection (50°C), mixing evenly, sterilizing at 121°C for 10 min, and cooling to room temperature to obtain a drug suspension;

[0087] S4, after filtering the auxiliary material solution through a filter membrane with a pore size of 0.22 μm, add it to the liquid preparation tank, then add the drug suspension, stir evenly, use a high-pressure homogenizer to homogenize 25 times at 40 MPa, fill the obtained suspension through a plastic bottle blowing, filling and sealing integrated machine, seal it, and obtain beclomethasone dipropionate suspension for inhalation.

[0088] After testing, the particle size of the beclomethasone dipropionate suspension for inhalation prepared in Examples 1 to 4 is 1 μm to 4 μm. The particle size of the beclomethasone dipropionate suspension for inhalation prepared in Example 5 is 2 μm to 9 μm.

[0089] This comparative example provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), which is different from Example 1 only in that polyethylene glycol hyaluronic acid is not added. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0090]

[0091] The preparation method of the beclomethasone dipropionate suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0092] Comparative Example 2

[0093] This comparative example provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), which is different from Example 1 only in that polysorbate-80 (II) is not added. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0094]

[0095] The preparation method of the beclomethasone dipropionate suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0096] Comparative Example 3

[0097] This comparative example provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), which differs from Example 1 only in that no The formula for preparing 110,000 suspension preparations is shown in the following table:

[0098]

[0099] The preparation method of the beclomethasone dipropionate suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0100] Comparative Example 4

[0101] This comparative example provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), which is different from Example 1 only in that polyethylene glycol hyaluronic acid is replaced with an equal amount of Tween 20. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0102]

[0103] The preparation method of the beclomethasone dipropionate suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0104] Comparative Example 5

[0105] This comparative example provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), which is different from Example 1 only in that the suspending agent is replaced with an equal amount of PVP k30. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0106]

[0107] The preparation method of the beclomethasone dipropionate suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0108] Comparative Example 6

[0109] This comparative example provides a beclomethasone dipropionate suspension for inhalation (specification: 0.8 mg: 2 mL), which is different from Example 1 only in that polysorbate-80 (II) is replaced with an equal amount of Tween 20. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0110]

[0111] The preparation method of the beclomethasone dipropionate suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0112] Quality Research

[0113] 1. Particle size distribution and redispersion turnover times

[0114] The beclomethasone dipropionate suspension for inhalation prepared in Example 1 and Comparative Examples 1 to 3 was tested for particle size distribution and redispersion turnover times.

[0115] The particle size distribution was determined by using a laser particle size analyzer: beclomethasone dipropionate suspension was taken and the sample was measured using a laser particle size analyzer, which was measured 3 times and its particle size distribution was recorded.

[0116] The test steps for the number of redispersion flips are as follows, and the results are shown in Table 1.

[0117] The beclomethasone dipropionate suspension for inhalation prepared in Example 1, the original research (Baolia, batch number 1135363) and comparative examples 1 to 3 were stored in an environment of 20 to 25 ° C and 40% humidity for 3 months, and then the suspension was quickly inverted 180°, stayed for 30 seconds, and then returned to the upright position, which was a flip experiment. After the flip test, the state of the suspension was observed. When the drug particles in the suspension were completely redispersed and no obvious precipitation or stratification was seen, the rotation operation was stopped and the number of rotations was recorded.

[0118] The judgment criteria for complete redispersion: the suspension presents a uniform appearance, with no visible aggregation or precipitation of drug particles, and the appearance of the suspension remains uniform after standing for 1 to 2 minutes. If precipitation or stratification occurs after standing, it means that the state of complete redispersion has not been achieved and the rotation operation needs to be continued.

[0119] Table 1 Particle size distribution and redispersion turnover times (n=3)

[0120]

[0121] 2. Aerodynamic particle size distribution

[0122] The aerodynamic particle size distribution of the beclomethasone dipropionate suspension for inhalation prepared in Example 1, the original research (Baolia, batch number 1164358) and comparative examples 1 to 3 was measured by NGI, and the specific steps were as follows:

[0123] The next generation cascade impaction (NGI) method was used. The NGI instrument was installed according to the device 5 in the 39th edition of the United States Pharmacopoeia 〈601〉. After checking that the airtightness was good, the vacuum pump was turned on. After the operation was stable, the flow meter was connected and the flow rate was adjusted to (28.3±1.5) L / min. The beclomethasone dipropionate suspension for inhalation of Example 1 was placed in an environment of (20±2)°C for at least 1h, shaken thoroughly, and poured into the nebulizer reservoir. The aerosol after atomization was connected to the adapter mouth of the NGI through a pipeline. The inhalation time was 5s, that is, after waiting for 5s, the atomized liquid was immediately reintroduced, and this operation was repeated until it was completed 10 times.

[0124] The first stage, 4-7 stage collection plates and MOC were cleaned with mobile phase respectively, and the washing liquid was combined into a 25 mL volumetric flask and diluted to the mark, and shaken well to be used as the test solution; the second and third stage collection plates were cleaned with mobile phase and diluted to the mark in a 10 mL volumetric flask, and shaken well to be used as the test solution. The reference substance was taken to prepare the reference solution, and the content of NGI at each level was determined by chromatography. The results of fine particle dose (FPD, <5 μm, μg), mass median aerodynamic diameter (MMDA) and geometric standard deviation (GSD) are shown in Table 2.

[0125] Table 2 Results of effective deposition rate measured by NGI (n=3)

[0126] Different prescriptions FPD(<5μm,μg) MMDA(μm) GSD Example 1 0.096±0.03 2.98±0.04 2.12±0.04 Original research 0.087±0.02 3.40±0.05 2.98±0.05 Comparative Example 1 0.045±0.03 11.34±0.06 4.65±0.27 Comparative Example 2 0.056±0.04 7.89±0.04 3.78±0.15 Comparative Example 3 0.061±0.03 5.34±0.05 6.90±0.16

[0127] 3. Effective lung deposition rate

[0128] The beclomethasone dipropionate suspension for inhalation prepared in Example 1, the original research (Baolia, batch number 1135776) and comparative examples 1 to 3 were atomized by a medical nebulizer, and the atomized aerosol was connected to the respiratory tract of the mouse. When the atomized liquid was exhausted, the atomization was stopped, and the mouse was euthanized. 0.5 g of lung tissue was obtained by dissection, 1 mL of water was added, and the tissue was homogenized by a tissue homogenizer. After extraction with 1 mL of ethyl acetate, 0.3 mL of mobile phase (acetonitrile and water in a volume ratio of 70:30) was added to dissolve, and then centrifuged in a high-speed centrifuge (10000 rpm, 10 min), the supernatant was taken, and the drug content was determined by liquid chromatography-mass spectrometry, and the effective lung deposition rate was calculated. The results are shown in Table 3.

[0129] Table 3 Effective lung deposition rate (n=5)

[0130] Different prescriptions Deposition rate of effective parts / % Example 1 22.04±6.68 Original research 21.59±4.22 Comparative Example 1 14.62±2.49 Comparative Example 2 11.78±2.03 Comparative Example 3 14.67±2.74

[0131] 4. Stability test

[0132] The beclomethasone dipropionate suspensions for inhalation prepared in Example 1, the original research (Baolia, batch number 1135776) and Comparative Examples 1 to 6 were placed at 25° C. and RH 40% for different time periods, and their particle size changes and content changes were tested. The results are shown in Table 4.

[0133] Table 4 Changes in particle size and content after placement for different time periods

[0134]

[0135]

[0136] 5. Cytotoxicity Assay

[0137] The beclomethasone dipropionate suspensions prepared in Example 1, the original research (Baolia, batch number 1135776) and Comparative Examples 4 to 6 were subjected to erythrocyte toxicity test. The specific steps are as follows and the results are shown in Table 5.

[0138] Erythrocyte toxicity test:

[0139] Preparation of 1% blood cell suspension: Take 2mL of rabbit ear vein blood, place it in a beaker, and gently stir it in the same direction with a glass rod wrapped with cotton to remove fibrin, transfer it to a centrifuge tube, add physiological saline solution to 10mL, centrifuge at 2500rpm for 5min, discard the upper layer, add physiological saline solution, centrifuge, repeat 4 to 5 times until the upper layer is clear. Take out the centrifuge tube and accurately read the blood cell volume, add physiological saline solution, shake gently to mix, and prepare 1% blood cell suspension for use.

[0140] Take a graduated centrifuge tube, add 2.5mL of 1% blood cell suspension and 3.5mL of physiological saline solution, shake gently to mix, then add 2mL of beclomethasone dipropionate suspension, shake gently until the blood cells are fully suspended, centrifuge for 10min (3000rpm), take the supernatant, use physiological saline solution as blank solution, measure the absorbance value of each group at 575nm by colorimetry, and calculate the average value. Use the corresponding reagent as the control group for determination; finally, bring it into the hemolysis rate calculation formula to calculate the hemolysis rate, n=5.

[0141] Positive control group: 1% Triton X-100 was used instead of the test sample;

[0142] Negative control group: 0.9% saline was used instead of the test sample;

[0143] Hemolysis rate (%) = (OD 待测 -OD 阴性 ) / (OD 阳性 -OD阴性 )×100%

[0144] Table 5 Red blood cell toxicity test (n=5)

[0145] Different prescriptions Hemolysis rate / % Example 1 0.05±0.01 Original research 0.05±0.02 Comparative Example 4 1.31±0.04 Comparative Example 5 0.52±0.03 Comparative Example 6 1.04±0.07

[0146] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A beclomethasone dipropionate suspension for inhalation, characterized in that: Including beclomethasone dipropionate, polyethylene glycol hyaluronic acid, polysorbate 80 (Ⅱ) and colloidal microcrystalline cellulose.

2. The beclomethasone dipropionate suspension for inhalation according to claim 1, characterized in that It also includes isotonicity regulators, pH regulators and water for injection.

3. The beclomethasone dipropionate suspension for inhalation according to claim 2, characterized in that, The invention comprises the following components in parts by weight: 1 part of beclomethasone dipropionate, 0.5 to 1.5 parts of polyethylene glycol hyaluronic acid, 0.05 to 0.3 parts of polysorbate 80 (II), 0.3 to 0.7 parts of colloidal microcrystalline cellulose, 19 to 23 parts of isotonicity regulator, 0.01 to 0.1 parts of pH regulator and 2490 to 2510 parts of water for injection.

4. The beclomethasone dipropionate suspension for inhalation according to claim 3, characterized in that The invention comprises the following components in parts by weight: 1 part of beclomethasone dipropionate, 1 part of polyethylene glycol hyaluronic acid, 0.2 part of polysorbate 80 (II), 0.5 part of colloidal microcrystalline cellulose, 22.5 parts of isotonicity regulator, 0.05 part of pH regulator and 2500 parts of water for injection.

5. The beclomethasone dipropionate suspension for inhalation according to any one of claims 1 to 4, characterized in that The molecular weight of hyaluronic acid in the polyethylene glycol hyaluronic acid is 5000Da-12000Da, and the molecular weight of polyethylene glycol is 2000Da-4000Da.

6. The beclomethasone dipropionate suspension for inhalation according to any one of claims 1 to 4, characterized in that The colloidal microcrystalline cellulose is selected from CL-611.

7. The beclomethasone dipropionate suspension for inhalation according to any one of claims 2 to 4, characterized in that The isotonicity adjusting agent is sodium chloride.

8. The beclomethasone dipropionate suspension for inhalation according to any one of claims 2 to 4, characterized in that The pH regulator is sodium hydroxide.

9. A method for preparing the beclomethasone dipropionate suspension for inhalation according to any one of claims 2 to 8, characterized in that: The steps include: S1, dissolving 99% to 99.5% of the prescribed amount of polyethylene glycol hyaluronic acid in the first part of the injection water to obtain a polyethylene glycol hyaluronic acid solution; Dissolving the prescribed amount of polysorbate 80(II) in the second portion of water for injection to obtain a polysorbate 80(II) solution; dissolving the prescribed amount of colloidal microcrystalline cellulose in the third portion of water for injection to obtain a colloidal microcrystalline cellulose solution; S2, mixing the polyethylene glycol hyaluronic acid solution, polysorbate 80 solution and colloidal microcrystalline cellulose solution evenly, adding a prescribed amount of an isotonicity adjusting agent, mixing evenly, then adding a pH adjusting agent to adjust the pH to 4-6, filtering and sterilizing, and obtaining an auxiliary material solution; S3, dissolving the remaining polyethylene glycol hyaluronic acid in the remaining water for injection, adding the prescribed amount of beclomethasone dipropionate, mixing evenly, sterilizing, adding the auxiliary material solution, mixing evenly, high pressure homogenizing, filling, and obtaining the beclomethasone dipropionate suspension for inhalation.

10. The method for preparing the beclomethasone dipropionate suspension for inhalation according to claim 9, characterized in that: The particle size of the beclomethasone dipropionate suspension for inhalation is 1 μm to 4 μm.

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