Budesonide suspension for inhalation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a budesonide suspension for inhalation and a preparation method thereof. The preparation method comprises the following steps: by taking sodium N-[8-(2-hydroxybenzoyl) amino] caprylate and phosphatidyl ethanolamine as surfactants, sodium taurodeoxycholate as a wetting agent and colloidal microcrystalline cellulose as a suspending aid, firstly, preparing an auxiliary material solution containing part of the surfactants, the wetting agent, the suspending aid and the like; the preparation method comprises the following steps: preparing a budesonide suspension for inhalation and a liquid medicine solution of budesonide and a surfactant, mixing the liquid medicine solution with an auxiliary material solution, and homogenizing at high pressure to prepare the budesonide suspension for inhalation. The prepared budesonide suspension has excellent storage stability and lung effective deposition rate, effectively solves the problems of coalescence of original traditional Chinese medicine particles and enlargement of the particle size of the medicine particles in the storage process, remarkably improves the stability of the preparation in the storage period, can realize good replacement of original products, and has a wide application prospect. High popularization and application values are realized.

Description

Technical Field

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

[0002] As a common chronic inflammatory airway disease, the number of asthma patients is huge and on the rise worldwide. As asthma attacks are recurrent, patients need to receive standardized treatment on a daily basis to control the condition and reduce the number of acute attacks. If asthma is not well controlled, acute attacks will not only cause pain to patients, but in severe cases, they may even be life-threatening.

[0003] As a glucocorticoid, budesonide has a unique chemical structure and pharmacological properties. It has high lipid solubility and can quickly pass through the cell membrane, bind to the glucocorticoid receptor in the cell, form a complex and enter the cell nucleus, regulate the transcription of inflammation-related genes, and thus exert a powerful anti-inflammatory effect. In inhaled therapy, budesonide can effectively inhibit the aggregation and activation of airway inflammatory cells, reduce the release of inflammatory mediators, reduce airway hyperresponsiveness, relieve airway spasm, and improve the patient's respiratory function. Compared with systemic glucocorticoids, inhaled budesonide suspension can achieve higher drug concentrations locally in the airways, while the amount of drug entering the blood circulation is less, which significantly reduces the risk of systemic adverse reactions and improves the safety of treatment and patient tolerance. Therefore, inhaled budesonide suspension has become a first-line drug for the treatment of asthma and is widely used in clinical practice.

[0004] The particle size uniformity of budesonide suspension is a key factor in determining its efficacy. At present, the particle size distribution of budesonide suspension is wide, and some larger particles cannot effectively reach the lungs, while smaller particles may be expelled from the body with exhaled air, reducing the lung deposition rate of the drug. On the other hand, during storage, the budesonide particles in the suspension are also prone to agglomeration and crystallization, resulting in poor particle size uniformity and affecting drug efficacy. Therefore, it is urgent to develop a new preparation process for budesonide suspension with uniform particle size, no crystallization during storage, narrow particle size range, and industrial mass production. Summary of the invention

[0005] Aiming at the problems that the existing budesonide suspension for inhalation has a wide particle size distribution, resulting in a low lung deposition rate and poor storage stability, the present invention provides a budesonide 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 budesonide suspension for inhalation, comprising budesonide, a surfactant, a wetting agent and a suspending agent;

[0008] The surfactant comprises sodium N-[8-(2-hydroxybenzoyl)amino]caprylate and phosphatidylethanolamine; the wetting agent is sodium taurodeoxycholate; and the suspending agent is colloidal microcrystalline cellulose.

[0009] Compared with the prior art, the budesonide suspension for inhalation provided by the present invention selects sodium N-[8-(2-hydroxybenzoyl)amino]octanoate and phosphatidylethanolamine as composite surfactants, wherein sodium N-[8-(2-hydroxybenzoyl)amino]octanoate can effectively reduce the surface tension between budesonide particles and the dispersion medium, making budesonide easier to disperse in the suspension and reducing the particle aggregation phenomenon; phosphatidylethanolamine can maintain the dispersion state of budesonide particles, enhance the stability of the entire suspension system, and improve the uniform dispersion of drug particles during storage and use; sodium taurodeoxycholate is selected as a wetting agent, which can effectively prevent budesonide particles with high fat solubility from being precipitated due to hydrophobic effect during preparation and storage. The invention discloses a kind of suspending agent, which can form a three-dimensional network structure in the suspension, and evenly wrap the budesonide particles therein, thereby preventing the particles from settling and agglomerating, thereby effectively improving the aggregation of the suspension particles and reducing the number of redispersion flipping times of the suspension. In addition, the colloidal microcrystalline cellulose can stabilize the structure of the droplets after the suspension is atomized, and prevent the droplets from breaking or deforming due to evaporation or collision during flight, thereby ensuring that the droplets can reach the lungs intact and effectively deposit the drug in the lung tissue, thereby improving the effective lung deposition rate.

[0010] The present invention constructs a stable budesonide suspension system with specific surfactants, wetting agents and suspending agents, improves the dispersibility and particle size distribution of drug particles in the suspension, is conducive to allowing more drugs to reach the lung lesions, and improves the lung deposition rate; at the same time, the suspension can always maintain a stable appearance and uniform drug distribution during long-term storage and transportation, and when performing a redispersion operation before each use, the drug particles can quickly recover to a uniform suspension state with simple shaking, ensuring that the drug dosage inhaled by the patient each time is accurate and consistent, greatly improving the reliability of the treatment effect.

[0011] Furthermore, the mass ratio of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate to phosphatidylethanolamine is (1.5-3):1.

[0012] Compared with a single conventional surfactant, the combination of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate and phosphatidylethanolamine can better improve the surface properties of drug particles, enhance the hydrophilicity of the particles, and help form a more stable suspension system, thereby improving the stability of the drug and the accuracy of dosage.

[0013] Furthermore, the colloidal microcrystalline cellulose is selected from NEO-C81.

[0014] Colloidal microcrystalline cellulose can form a three-dimensional network structure in the suspension, evenly wrapping the budesonide particles in it to prevent the particles from settling and aggregating. At the same time, colloidal microcrystalline cellulose can provide a certain viscosity, so that the suspension has good fluidity and stability, ensuring that the drug particles will not settle quickly during storage, thereby ensuring the accuracy of each dose.

[0015] Furthermore, the budesonide suspension for inhalation also includes a metal ion complexing agent, an osmotic pressure regulator, buffer salts and water for injection.

[0016] Exemplarily, the buffer salt is citric acid-sodium citrate.

[0017] Exemplarily, the metal ion complexing agent is disodium edetate.

[0018] Exemplarily, the osmotic pressure regulator is sodium chloride.

[0019] It should be noted that the present invention may also use other osmotic pressure regulators, buffer salts and metal ion complexing agents that are conventionally acceptable in the pharmaceutical field, and the present invention does not make any special limitations.

[0020] Furthermore, the budesonide suspension for inhalation comprises the following components in parts by mass: 1 part of budesonide, 0.5 to 0.7 parts of a surfactant, 0.3 to 0.5 parts of a wetting agent, 0.1 to 0.3 parts of a suspending agent, 0.1 to 0.3 parts of a metal ion complexing agent, 1.4 to 1.8 parts of a buffer salt, 15 to 19 parts of an osmotic pressure regulator, and 1999 to 2001 parts of water for injection.

[0021] Furthermore, the budesonide suspension for inhalation comprises the following components in parts by mass: 1 part of budesonide, 0.6 parts of surfactant, 0.4 parts of wetting agent, 0.2 parts of suspending agent, 0.2 parts of metal ion complexing agent, 1.7 parts of buffer salt, 17 parts of osmotic pressure regulator and 2000 parts of water for injection.

[0022] The present invention also provides a method for preparing the above-mentioned budesonide suspension for inhalation, comprising the following steps:

[0023] S1, dissolving 93% to 97% of the prescribed amount of surfactant, the prescribed amount of wetting agent, the prescribed amount of suspending agent, the prescribed amount of buffer salt, and the prescribed amount of metal ion complexing agent in part of the water for injection, then mixing the obtained solutions evenly, adding the prescribed amount of osmotic pressure regulator, filtering and sterilizing, and obtaining an excipient solution;

[0024] S2, dissolving the remaining surfactant in part of the water for injection, then adding the prescribed amount of budesonide, mixing evenly, sterilizing, adding the excipient solution and the remaining water for injection, high pressure homogenizing, filling, and obtaining the budesonide suspension for inhalation.

[0025] The preparation method of the budesonide suspension for inhalation provided by the present invention comprises the following steps: firstly, a part of a surfactant, a prescribed amount of a wetting agent, a suspending agent, a buffer salt and a metal ion complexing agent 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 the budesonide, so that the surface of the budesonide particles can be fully covered by the surfactant, so that the mutual collision and agglomeration between the drug particles can be prevented, and the surface properties of the drug particles can be adjusted, so that the affinity of the drug particles with water for injection is increased, so that the system is more conducive to the dispersion of the drug particles, so that the particle size of the drug particles is more uniform, which is conducive to maintaining a stable dispersion state during subsequent storage and use.

[0026] Furthermore, the temperature of the water for injection used in the preparation process is 40°C to 45°C.

[0027] It should be noted that the budesonide raw material used in the present invention is micronized budesonide with a particle size of 0.8 to 4.5 μm.

[0028] Furthermore, in S1, the amount of water for injection for dissolving the surfactant is 2% to 3% of the prescribed amount; the amount of water for injection for dissolving the wetting agent is 2% to 3% of the prescribed amount; the amount of water for injection for dissolving the suspending agent is 4% to 5% of the prescribed amount; the amount of water for injection for dissolving the buffer salt is 4% to 5% of the prescribed amount; the amount of water for injection for dissolving the metal ion complexing agent is 4% to 5% of the prescribed amount.

[0029] Furthermore, in S1, the pore size of the filter membrane used for filtration sterilization is 0.22 μm.

[0030] Furthermore, in S2, the amount of water for injection used to dissolve the remaining surfactant is 0.1% to 0.2% of the prescribed amount.

[0031] Furthermore, in S2, the sterilization temperature is 121° C., and the sterilization time is 10 min to 15 min.

[0032] Furthermore, in S2, the pressure of the high-pressure homogenization is 20 MPa to 50 MPa, and the number of homogenization times is 20 to 50 times.

[0033] Exemplarily, in S2, a bottle blowing, filling and sealing machine is used for filling and sealing.

[0034] Exemplarily, in S2, the volume of each single-dose package is 2.05-2.22 mL.

[0035] Furthermore, the particle size of the budesonide suspension for inhalation is 1 μm to 5 μm.

[0036] The invention uses sodium N-[8-(2-hydroxybenzoyl)amino]octanoate and phosphatidylethanolamine as surfactants, sodium taurodeoxycholate 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 budesonide and the surfactant, then mixes the drug solution with the auxiliary material solution and homogenizes under high pressure to prepare a budesonide suspension for inhalation. The prepared budesonide suspension has excellent storage stability and effective lung deposition rate, effectively solves the problems of drug particle agglomeration in the original research and the enlargement of drug particle size during storage, significantly improves the stability of the preparation during storage, can achieve a good replacement of the original research product, and has a simple preparation process, good repeatability, easy to achieve industrial mass production, and high promotion and application value. DETAILED DESCRIPTION

[0037] 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.

[0038] In order to better illustrate the present invention, further examples are given below.

[0039] The budesonide raw material used in the following examples is micronized budesonide with a particle size of 0.8 to 4.5 μm.

[0040] The original preparation used below is Pulmicort Respules, batch number 327572.

[0041] Example 1

[0042] This embodiment provides a budesonide suspension for inhalation (specification: 1 mg: 2 mL), and the prescription for preparing 110,000 suspension preparations is shown in the following table:

[0043]

[0044] The preparation method of the above-mentioned budesonide suspension for inhalation is as follows:

[0045] S1, taking 95% of the prescribed amount of surfactant and adding it to 2.27% of the prescribed amount of water for injection (40-45° C.), dissolving it to obtain a surfactant solution;

[0046] Take the prescribed amount of wetting agent and add it to 2.27% of the prescribed amount of water for injection (40-45°C), dissolve it to obtain a wetting agent solution;

[0047] Take the prescribed amount of suspending agent and add it into 4.55% of the prescribed amount of water for injection (40-45° C.), dissolve it, and obtain a suspending agent solution;

[0048] Take the prescribed amount of buffered salt and add it to 4.55% of the prescribed amount of water for injection (40-45°C), dissolve it and obtain a buffered salt solution;

[0049] Take the prescribed amount of metal ion complexing agent and add it into 4.55% of the prescribed amount of water for injection (40-45° C.), dissolve it, and obtain a metal ion complexing agent solution;

[0050] S2, adding the above-mentioned surfactant solution, wetting agent solution, suspending agent solution, buffer salt solution and metal ion complexing agent solution into a liquid preparation tank, adding a prescribed amount of osmotic pressure regulator, stirring magnetically to dissolve, and adjusting the water temperature to 40-45° C. to obtain an auxiliary material solution;

[0051] S3, adding the remaining surfactant to 0.1045% of the prescribed amount of water for injection (40-45° C.), stirring to dissolve, adding the prescribed amount of budesonide, mixing evenly, sterilizing at 121° C. for 10 min, and cooling to room temperature to obtain a drug suspension;

[0052] 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 above-mentioned drug suspension and the remaining water for injection, stir evenly, and homogenize it 25 times at 40 MPa by a high-pressure homogenizer. Fill the obtained suspension through a plastic bottle blowing, filling and sealing integrated machine, seal it, and obtain budesonide suspension for inhalation.

[0053] Example 2

[0054] This embodiment provides a budesonide suspension for inhalation (specification: 1 mg: 2 mL), and the prescription for preparing 110,000 suspension preparations is shown in the following table:

[0055]

[0056]

[0057] The preparation method of the above-mentioned budesonide suspension for inhalation is as follows:

[0058] S1, taking 95% of the prescribed amount of surfactant and adding it to 2.15% of the prescribed amount of water for injection (40-45° C.), dissolving it to obtain a surfactant solution;

[0059] Take the prescribed amount of wetting agent and add it to 2.15% of the prescribed amount of water for injection (40-45°C), dissolve it to obtain a wetting agent solution;

[0060] Take the prescribed amount of suspending agent and add it into 4.26% of the prescribed amount of water for injection (40-45° C.), dissolve it, and obtain a suspending agent solution;

[0061] Take the prescribed amount of buffered salt and add it to 4.26% of the prescribed amount of water for injection (40-45°C), dissolve it and obtain a buffered salt solution;

[0062] Take the prescribed amount of metal ion complexing agent and add it into 4.26% of the prescribed amount of water for injection (40-45° C.), dissolve it, and obtain a metal ion complexing agent solution;

[0063] S2, adding the above-mentioned surfactant solution, wetting agent solution, suspending agent solution, buffer salt solution and metal ion complexing agent solution into a liquid preparation tank, adding a prescribed amount of osmotic pressure regulator, stirring magnetically to dissolve, and adjusting the water temperature to 40-45° C. to obtain an auxiliary material solution;

[0064] S3, adding the remaining surfactant to 0.11% of the prescribed amount of water for injection (40-45° C.), stirring to dissolve, adding the prescribed amount of budesonide, mixing evenly, sterilizing at 121° C. for 10 min, and cooling to room temperature to obtain a drug suspension;

[0065] S4, after filtering the auxiliary material solution through a filter membrane with a pore size of 0.22 μm, add it to a liquid preparation tank, then add the above-mentioned drug suspension and the remaining water for injection, stir evenly, and homogenize it 30 times at 30 MPa using a high-pressure homogenizer. Fill the obtained suspension through a plastic bottle blowing, filling and sealing integrated machine, seal it, and obtain budesonide suspension for inhalation.

[0066] Example 3

[0067] This embodiment provides a budesonide suspension for inhalation (specification: 1 mg: 2 mL), and the prescription for preparing 110,000 suspension preparations is shown in the following table:

[0068]

[0069] The preparation method of the above-mentioned budesonide suspension for inhalation is as follows:

[0070] S1, taking 95% of the prescribed amount of surfactant and adding it to 2.89% of the prescribed amount of water for injection (40-45° C.), dissolving it to obtain a surfactant solution;

[0071] Take the prescribed amount of wetting agent and add it to 2.93% of the prescribed amount of water for injection (40-45°C), dissolve it to obtain a wetting agent solution;

[0072] Take the prescribed amount of suspending agent and add it into 4.96% of the prescribed amount of water for injection (40-45° C.), dissolve it, and obtain a suspending agent solution;

[0073] Take the prescribed amount of buffered salt and add it to 4.96% of the prescribed amount of water for injection (40-45°C), dissolve it and obtain a buffered salt solution;

[0074] Take the prescribed amount of metal ion complexing agent and add it into 4.96% of the prescribed amount of water for injection (40-45° C.), dissolve it, and obtain a metal ion complexing agent solution;

[0075] S2, adding the above-mentioned surfactant solution, wetting agent solution, suspending agent solution, buffer salt solution and metal ion complexing agent solution into a liquid preparation tank, adding a prescribed amount of osmotic pressure regulator, stirring magnetically to dissolve, and adjusting the water temperature to 40-45° C. to obtain an auxiliary material solution;

[0076] S3, adding the remaining surfactant to 0.19% of the prescribed amount of water for injection (40-45° C.), stirring to dissolve, adding the prescribed amount of budesonide, mixing evenly, sterilizing at 121° C. for 10 min, and cooling to room temperature to obtain a drug suspension;

[0077] S4, filtering the auxiliary material solution through a filter membrane with a pore size of 0.22 μm, adding it to a liquid preparation tank, and then adding the above-mentioned drug suspension and the remaining water for injection, stirring evenly, homogenizing it 20 times at 50 MPa with a high-pressure homogenizer, filling the obtained suspension with a plastic bottle blowing, filling and sealing integrated machine, and sealing it to obtain budesonide suspension for inhalation.

[0078] Example 4

[0079] This embodiment provides a budesonide suspension for inhalation (specification: 1 mg: 2 mL), and the prescription for preparing 110,000 suspension preparations is shown in the following table:

[0080]

[0081]

[0082] The preparation method of the above-mentioned budesonide suspension for inhalation is as follows:

[0083] S1, taking 95% of the prescribed amount of surfactant and adding it to 2.27% of the prescribed amount of water for injection (40-45° C.), dissolving it to obtain a surfactant solution;

[0084] Take the prescribed amount of wetting agent and add it to 2.27% of the prescribed amount of water for injection (40-45°C), dissolve it to obtain a wetting agent solution;

[0085] Take the prescribed amount of suspending agent and add it into 4.55% of the prescribed amount of water for injection (40-45° C.), dissolve it, and obtain a suspending agent solution;

[0086] Take the prescribed amount of buffered salt and add it to 4.55% of the prescribed amount of water for injection (40-45°C), dissolve it and obtain a buffered salt solution;

[0087] Take the prescribed amount of metal ion complexing agent and add it into 4.55% of the prescribed amount of water for injection (40-45° C.), dissolve it, and obtain a metal ion complexing agent solution;

[0088] S2, adding the above-mentioned surfactant solution, wetting agent solution, suspending agent solution, buffer salt solution and metal ion complexing agent solution into a liquid preparation tank, adding a prescribed amount of osmotic pressure regulator, stirring magnetically to dissolve, and adjusting the water temperature to 40-45° C. to obtain an auxiliary material solution;

[0089] S3, adding the remaining surfactant to 0.1045% of the prescribed amount of water for injection (40-45° C.), stirring to dissolve, adding the prescribed amount of budesonide, mixing evenly, sterilizing at 121° C. for 10 min, and cooling to room temperature to obtain a drug suspension;

[0090] 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 above-mentioned drug suspension and the remaining water for injection, stir evenly, and homogenize it 25 times at 40 MPa by a high-pressure homogenizer. Fill the obtained suspension through a plastic bottle blowing, filling and sealing integrated machine, seal it, and obtain budesonide suspension for inhalation.

[0091] Comparative Example 1

[0092] This comparative example provides a budesonide suspension (specification: 1 mg: 2 mL), which differs from Example 1 only in that no surfactant is added. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0093]

[0094] The preparation method of the above budesonide suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0095] Comparative Example 2

[0096] This comparative example provides a budesonide suspension (specification: 1 mg: 2 mL), which differs from Example 1 only in that no wetting agent is added. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0097]

[0098]

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

[0100] Comparative Example 3

[0101] This comparative example provides a budesonide suspension (specification: 1 mg: 2 mL), which differs from Example 1 only in that no suspending agent is added. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0102]

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

[0104] Comparative Example 4

[0105] This comparative example provides a budesonide suspension (specification: 1 mg: 2 mL), which is different from Example 1 only in that the surfactant is replaced with an equal amount of polyoxyethylene hydrogenated castor oil. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0106]

[0107]

[0108] The preparation method of the above budesonide suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0109] Comparative Example 5

[0110] This comparative example provides a budesonide suspension (specification: 1 mg: 2 mL), which is different from Example 1 only in that the suspending agent is replaced with an equal amount of hydroxypropyl cellulose K4M. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0111]

[0112] The preparation method of the above budesonide suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0113] Comparative Example 6

[0114] This comparative example provides a budesonide suspension (specification: 1 mg: 2 mL), which differs from Example 1 only in that the wetting agent is replaced with an equal amount of glycerol. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0115]

[0116] The preparation method of the above budesonide suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0117] Comparative Example 7

[0118] This comparative example provides a budesonide suspension (specification: 1 mg: 2 mL), which is different from Example 1 only in that the surfactant is replaced with a single sodium N-[8-(2-hydroxybenzoyl)amino]octanoate. The prescription for preparing 110,000 suspension preparations is shown in the following table:

[0119]

[0120]

[0121] The preparation method of the above budesonide suspension for inhalation is the same as that in Example 1, which will not be repeated here.

[0122] Quality Research

[0123] 1. Particle size distribution and redispersion turnover times

[0124] The budesonide suspension for inhalation prepared in Example 1 and Comparative Examples 1 to 3 were tested for particle size distribution and redispersion turnover times. The results are shown in Table 1.

[0125] The particle size distribution was determined by using a laser particle size analyzer: the budesonide suspension was taken and the sample was measured using a laser particle size analyzer, and the measurement was performed 3 times to record the particle size distribution.

[0126] The test steps for the number of redistribution flips are as follows:

[0127] The budesonide suspension for inhalation prepared in Example 1, the original research and comparative examples 1 to 3 was stored in an environment of 20 to 25 ° C and a humidity of 40% 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 test. 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.

[0128] 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.

[0129] Table 1 Particle size distribution and redispersion turnover times (n=3)

[0130]

[0131]

[0132] 2. Aerodynamic particle size distribution

[0133] The aerodynamic particle size distribution of the budesonide suspension for inhalation prepared in Example 1, original research and Comparative Examples 1 to 3 was measured by NGI, and the specific steps were as follows:

[0134] 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 budesonide suspension for inhalation of Example 1 was placed in an environment of (20±2)°C for at least 1 hour, 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.

[0135] 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.

[0136] Table 2 Results of effective deposition rate measured by NGI (n=3)

[0137]

[0138]

[0139] 3. Effective lung deposition rate

[0140] The budesonide suspension for inhalation prepared in Example 1, the original research and comparative examples 1 to 3 were atomized by a medical atomizer, 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.

[0141] Table 3 Effective lung deposition rate (n=5)

[0142] Different prescriptions Deposition rate of effective parts / % Example 1 27.04±6.68 Original research 23.59±4.22 Comparative Example 1 14.62±2.31 Comparative Example 2 11.34±2.87 Comparative Example 3 14.73±2.65

[0143] 4. Stability test

[0144] The budesonide suspensions for inhalation prepared in Example 1, original research and Comparative Examples 1 to 7 were placed at 25° C. and RH 40% for different periods of time, and their particle size changes and content changes were tested. The results are shown in Table 4.

[0145] Table 4 Changes in particle size and content after placement for different time periods

[0146]

[0147] 5. Cytotoxicity Assay

[0148] The budesonide suspensions prepared in Example 1, the original research and Comparative Examples 4 to 6 were subjected to a red blood cell toxicity test. The specific steps are as follows and the results are shown in Table 5.

[0149] Erythrocyte toxicity test:

[0150] 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.

[0151] 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 budesonide 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, enter the hemolysis rate calculation formula to calculate the hemolysis rate, n=5.

[0152] Positive control group: 1% Triton X-100 was used instead of the test sample;

[0153] Negative control group: 0.9% saline was used instead of the test sample;

[0154] Hemolysis rate (%) = (OD 待测 -OD 阴性) / (OD 阳性 -OD 阴性 )×100%

[0155] Table 5 Red blood cell toxicity test (n=5)

[0156] Different prescriptions Hemolysis rate / % Example 1 0.03±0.01 Original research 0.03±0.02 Comparative Example 4 1.54±0.02 Comparative Example 5 0.47±0.05 Comparative Example 6 1.12±0.06

[0157] The budesonide suspensions prepared in Examples 2 to 4 can achieve the same technical effects as Example 1.

[0158] 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 budesonide suspension for inhalation, characterized in that: including budesonide, surfactant, wetting agent and suspending agent; The surfactant comprises sodium N-[8-(2-hydroxybenzoyl)amino]caprylate and phosphatidylethanolamine; the wetting agent is sodium taurodeoxycholate; and the suspending agent is colloidal microcrystalline cellulose.

2. The budesonide suspension for inhalation according to claim 1, characterized in that The mass ratio of sodium N-[8-(2-hydroxybenzoyl)amino]caprylate to phosphatidylethanolamine is (1.5-3):

1.

3. The budesonide suspension for inhalation according to claim 1, characterized in that The colloidal microcrystalline cellulose is selected from 4. The budesonide suspension for inhalation according to any one of claims 1 to 3, characterized in that It also includes metal ion complexing agents, osmotic pressure regulators, buffer salts and water for injection.

5. The budesonide suspension for inhalation according to claim 4, characterized in that The metal ion complexing agent is disodium edetate.

6. The budesonide suspension for inhalation according to claim 4, characterized in that The osmotic pressure regulator is sodium chloride; and / or The buffer salt is citric acid-sodium citrate.

7. The budesonide suspension for inhalation according to claim 4, characterized in that The invention comprises the following components in parts by weight: 1 part of budesonide, 0.5 to 0.7 parts of surfactant, 0.3 to 0.5 parts of wetting agent, 0.1 to 0.3 parts of suspending agent, 0.1 to 0.3 parts of metal ion complexing agent, 1.4 to 1.8 parts of buffer salt, 15 to 19 parts of osmotic pressure regulator and 1999 to 2001 parts of water for injection.

8. The budesonide suspension for inhalation according to claim 7, characterized in that The preparation comprises the following components in parts by weight: 1 part of budesonide, 0.6 parts of a surfactant, 0.4 parts of a wetting agent, 0.2 parts of a suspending agent, 0.2 parts of a metal ion complexing agent, 1.7 parts of a buffer salt, 17 parts of an osmotic pressure regulator and 2000 parts of water for injection.

9. A method for preparing the budesonide suspension for inhalation according to any one of claims 4 to 8, characterized in that: The steps include: S1, dissolving 93% to 97% of the prescribed amount of surfactant, the prescribed amount of wetting agent, the prescribed amount of suspending agent, the prescribed amount of buffer salt, and the prescribed amount of metal ion complexing agent in part of the water for injection, then mixing the obtained solutions evenly, adding the prescribed amount of osmotic pressure regulator, filtering and sterilizing, and obtaining an excipient solution; S2, dissolving the remaining surfactant in part of the water for injection, then adding the prescribed amount of budesonide, mixing evenly, sterilizing, adding the excipient solution and the remaining water for injection, high pressure homogenizing, filling, and obtaining the budesonide suspension for inhalation.

10. The method for preparing the budesonide suspension for inhalation according to claim 9, characterized in that: The particle size of the budesonide suspension for inhalation is 1 μm to 5 μm.

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