Beclomethasone propionate suspension for inhalation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a beclomethasone propionate suspension for inhalation and a preparation method thereof. The beclomethasone propionate suspension for inhalation comprises beclomethasone propionate, a suspending stabilizer and a propellant, and the preparation method comprises the steps of raw material crushing, suspending stabilizer pretreatment, dynamic circulating temperature control mixing, high-pressure homogenization and the like. The settling volume ratio of the suspension is obviously superior to that in the prior art. The preparation provided by the invention has excellent physical and chemical stability and loose storage conditions, and provides a safe and efficient inhalation preparation choice for the treatment of respiratory diseases.

Description

Technical Field

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

[0002] Beclomethasone dipropionate is a potent topical glucocorticoid with anti-inflammatory, anti-allergic, and antipruritic properties. It can inhibit bronchial exudates, reduce bronchial mucosal swelling, and relieve bronchospasm, playing a key role in the treatment of chronic and allergic asthma, allergic rhinitis, and other diseases. Beclomethasone dipropionate suspension for inhalation is its primary formulation.

[0003] Chinese patent publication number CN116036056A discloses a beclomethasone dipropionate suspension for inhalation and a preparation method thereof, wherein each 100 mL of the beclomethasone dipropionate suspension for inhalation is composed of 0.5 g to 3 g of beclomethasone dipropionate, 0.05 wt% to 0.3 wt% of Triton X-100, and water.

[0004] Chinese patent publication number CN119770463A discloses a beclomethasone dipropionate suspension for inhalation and a preparation method thereof. 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. An excipient solution containing a portion of the surfactant, wetting agent, and suspending agent, and a drug solution of beclomethasone dipropionate and the surfactant are first prepared. The drug solution and the excipient solution are then mixed and homogenized under high pressure to prepare the beclomethasone dipropionate suspension for inhalation.

[0005] Chinese patent publication number CN106137964A discloses a beclomethasone dipropionate suspension for inhalation, comprising beclomethasone dipropionate and an amino acid, particularly leucine or phenylalanine, to prepare an inhalable suspension aerosol pharmaceutical composition. The suspension aerosol maintains good suspension stability.

[0006] However, the existing technology has many deficiencies in the preparation and performance of the suspension, which limits its therapeutic effect and application range.

[0007] 1. Beclomethasone dipropionate drug particles in suspensions are unstable and prone to agglomeration and sedimentation. During storage, interactions between beclomethasone dipropionate particles within the suspension can cause agglomeration, resulting in poor particle size uniformity. This not only affects the uniform dispersion of the drug during atomization, making it difficult to accurately guarantee the dosage received by the patient each time the drug is inhaled, but can also cause uneven drug distribution, thereby impacting therapeutic efficacy. Patients may not achieve the desired therapeutic effect due to insufficient inhaled drug, or may experience adverse reactions due to inhaling excessive drug particles.

[0008] 2. Storage conditions are stringent, requiring it to be kept away from light and can only be stored for three months. Any remaining drug after use must be stored at 2-8°C. The drug particles in beclomethasone dipropionate suspension are susceptible to various environmental factors and can degrade. For example, when beclomethasone dipropionate suspension is stored at high temperatures, the decomposition rate of its active ingredient will be significantly accelerated, resulting in reduced efficacy.

[0009] 3. The selection and use of additives in the existing technology fail to fully consider their comprehensive impact on suspension stability, particle size distribution and drug efficacy, making it difficult to effectively optimize the performance of the suspension.

[0010] In summary, existing beclomethasone dipropionate suspensions for inhalation have significant drawbacks in terms of stability and additive usage. Developing a beclomethasone dipropionate suspension for inhalation and its preparation method that improves stability and other properties by optimizing additives and limiting drug particle size is of great practical significance and meets market demand. Summary of the Invention

[0011] The present invention provides a beclomethasone dipropionate suspension for inhalation and a preparation method thereof, and significantly improves the stability of the suspension by optimizing the prescription composition and the preparation process.

[0012] The beclomethasone dipropionate suspension for inhalation of the present invention is formulated as follows:

[0013] (1) Active ingredient: beclomethasone dipropionate (mass fraction 0.03-0.08%), particle size controlled to D90 < 5 μm (measured by laser particle size analyzer) to ensure that the drug particles can be effectively deposited in the respiratory tract.

[0014] (2) Suspension stabilizer: A ternary system consisting of sodium dioctyl sulfosuccinate (0.2-0.5%), leucine (0.8-1.5%), and guar gum (0.4-0.75%), which enhances the steric hindrance effect and anti-sedimentation ability of the suspension through synergistic action.

[0015] (3) Propellant: tetrafluoroethane and / or heptafluoropropane (balance), which provides atomization power and adjusts the system density.

[0016] The preparation method of beclomethasone dipropionate suspension for inhalation of the present invention is as follows:

[0017] (1) Raw material pretreatment: Use air flow milling process to grind beclomethasone dipropionate to D90 < 5 μm, control the ambient humidity ≤ 30%, and mix with propellant immediately after grinding to avoid moisture absorption and agglomeration.

[0018] (2) Suspending agent pretreatment:

[0019] Sodium dioctyl sulfosuccinate was dissolved in the propellant to form a homogeneous solution; leucine was sieved and ultrasonically dispersed in the propellant; guar gum was heated and dissolved and then gradually cooled (35-45°C → 30°C → 25°C, each stage for 10 minutes) to room temperature to promote the formation of a stable network structure of the polymer excipient.

[0020] (3) Preparation of suspension: After the pretreatment solution is mixed, it is treated by dynamic cycle temperature control (refrigeration at 5-10°C for 30-50 min, shaking at room temperature for 20-30 min, and cycled 2-4 times), and then homogenized at 80-100 MPa to ensure uniform dispersion of particles.

[0021] (4) Filling and sealing: Pressure fill the propellant to the full amount, mix thoroughly and seal.

[0022] Compared with the prior art, the technical effects of the present invention are:

[0023] 1. Significantly improved physical stability

[0024] The present invention utilizes a ternary suspension system of sodium dioctyl sulfosuccinate, leucine, and guar gum. Through the synergistic effects of surface energy reduction, steric hindrance, and a polymer network structure, the suspension's sedimentation volume ratio (F value) remains above 0.93 for 48 hours. Furthermore, the present invention utilizes a dynamic cycle temperature control process (alternating cycles of low-temperature refrigeration and room-temperature shaking) to further enhance dispersion uniformity, significantly improving stability compared to single temperature control or shaking processes.

[0025] 2. Chemical stability is significantly improved

[0026] The present invention adopts a gradient cooling dissolution process (35-45°C → 30°C → 25°C) to avoid the loss of effectiveness of auxiliary materials such as guar gum due to local overheating. Accelerated stability tests (40°C / 75% RH, 6 months) show that the content retention rate of the preparation of the present invention is ≥99.9%.

[0027] Through dual innovations in formulation and process, the present invention systematically solves the problems of poor stability, large fluctuations in efficacy, and inconvenient storage of existing beclomethasone dipropionate suspensions for inhalation. It provides a more reliable formulation option for the clinical treatment of respiratory diseases such as asthma and rhinitis, and has both technological advancement and market application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 : Stability of Examples 1-3, Comparative Examples 1-4, and commercially available preparations. DETAILED DESCRIPTION

[0029] In order to make the purpose and technical solution of the present invention more clear, the present invention is further described below in conjunction with the embodiments, but the scope of protection of the present invention is not limited to these embodiments, and the embodiments are only used to illustrate the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the scope of protection of the present invention.

[0030] Example 1 Beclomethasone dipropionate suspension for inhalation

[0031] formula:

[0032]

[0033] Preparation method:

[0034] (1) Pretreatment of beclomethasone dipropionate: Use air flow milling process, control the ambient humidity ≤30%, grind beclomethasone dipropionate to D90 <5μm, and immediately mix with an appropriate amount of propellant (a mixture of tetrafluoroethane and heptafluoropropane) after grinding to avoid moisture absorption and agglomeration.

[0035] (2) Pretreatment of suspending stabilizer: dissolve sodium dioctyl sulfosuccinate in an appropriate amount of propellant (a mixture of tetrafluoroethane and heptafluoropropane) to form a homogeneous solution, and set aside; leucine is pre-dispersed in a portion of the propellant (a mixture of tetrafluoroethane and heptafluoropropane) after passing through a 200-mesh sieve, and ultrasonic-assisted dispersion is performed for 10 to 15 minutes, and set aside; guar gum is mixed with an appropriate amount of propellant (a mixture of tetrafluoroethane and heptafluoropropane), heated to 40°C to fully dissolve, and cooled using a gradient cooling method. The gradient cooling method is to use a water bath to cool from 40°C → 30°C → 25°C, and each stage is 10 minutes to room temperature, and set aside.

[0036] (3) Preparation of suspension: The pretreated suspending stabilizer solution and beclomethasone dipropionate solution were mixed and subjected to dynamic cycle temperature control treatment (refrigeration at 8°C for 40 minutes, shaking at room temperature for 25 minutes, and three cycles), and then circulated four times using a high-pressure homogenizer (pressure of 100 MPa) to obtain a suspension.

[0037] (4) Filling and sealing: Use pressure filling method to fill the propellant to the full amount, ensure that the propellant and suspension are fully mixed, and seal.

[0038] It should be noted that the "appropriate amount of propellant" mentioned in the present invention means dissolution or dispersion, and the total amount should not exceed the total amount of propellant used, ensuring that the propellant is not excessive during filling.

[0039] Example 2 Beclomethasone dipropionate suspension for inhalation

[0040] formula:

[0041]

[0042]

[0043] Preparation method:

[0044] (1) Pretreatment of beclomethasone dipropionate: Use air flow milling process, control the ambient humidity ≤30%, grind beclomethasone dipropionate to D90 <5μm, and immediately mix with an appropriate amount of propellant after grinding to avoid moisture absorption and agglomeration.

[0045] (2) Pretreatment of suspending stabilizer: dissolve sodium dioctyl sulfosuccinate in an appropriate amount of propellant to form a homogeneous solution, and set aside; leucine is pre-dispersed in part of the propellant after passing through a 200-mesh sieve, and ultrasonic-assisted dispersion is performed for 10 to 15 minutes, and set aside; guar gum is mixed with an appropriate amount of propellant and heated to 35°C to fully dissolve, and cooled using a gradient cooling method. The gradient cooling method is to use a water bath to cool from 35°C → 30°C → 25°C, and each stage is 10 minutes to room temperature, and set aside.

[0046] (3) Preparation of suspension: The pretreated suspending stabilizer solution and beclomethasone dipropionate solution were mixed and subjected to dynamic cyclic temperature control treatment (refrigeration at 5°C for 30 minutes, shaking at room temperature for 20 minutes, and two cycles), and then cyclically treated three times using a high-pressure homogenizer (pressure of 80 MPa) to obtain a suspension.

[0047] (4) Filling and sealing: Use pressure filling method to fill the propellant to the full amount, ensure that the propellant and suspension are fully mixed, and seal.

[0048] Example 3 Beclomethasone dipropionate suspension for inhalation

[0049] formula:

[0050]

[0051] Preparation method:

[0052] (1) Pretreatment of beclomethasone dipropionate: Use air flow milling process, control the ambient humidity ≤30%, grind beclomethasone dipropionate to D90 <5μm, and immediately mix with an appropriate amount of propellant after grinding to avoid moisture absorption and agglomeration.

[0053] (2) Pretreatment of suspending stabilizer: dissolve sodium dioctyl sulfosuccinate in an appropriate amount of propellant to form a homogeneous solution, and set aside; leucine is pre-dispersed in part of the propellant after passing through a 200-mesh sieve, and ultrasonic-assisted dispersion is performed for 10 to 15 minutes, and set aside; guar gum is mixed with an appropriate amount of propellant and heated to 45°C to fully dissolve, and cooled using a gradient cooling method. The gradient cooling method is to use a water bath to cool from 45°C to 30°C to 25°C, and each stage is 10 minutes to room temperature, and set aside.

[0054] (3) Preparation of suspension: The pretreated suspending stabilizer solution and beclomethasone dipropionate solution were mixed and subjected to dynamic cycle temperature control treatment (refrigeration at 10°C for 50 minutes, shaking at room temperature for 30 minutes, and four cycles), and then circulated for five times using a high-pressure homogenizer (pressure of 100 MPa) to obtain a suspension.

[0055] (4) Filling and sealing: Use pressure filling method to fill the propellant to the full amount, ensure that the propellant and suspension are fully mixed, and seal.

[0056] Comparative Example 1 Beclomethasone dipropionate suspension for inhalation

[0057] formula:

[0058]

[0059] Preparation method:

[0060] (1) Pretreatment of beclomethasone dipropionate: Use air flow milling process, control the ambient humidity ≤30%, grind beclomethasone dipropionate to D90 <5μm, and immediately mix with an appropriate amount of propellant after grinding to avoid moisture absorption and agglomeration.

[0061] (2) Pretreatment of suspending stabilizer: leucine was pre-dispersed in part of the propellant after passing through a 200-mesh sieve, and ultrasonic-assisted dispersion was performed for 10 to 15 minutes, and the mixture was set aside. Guar gum was mixed with an appropriate amount of propellant and heated to 40°C to fully dissolve, and then cooled using a gradient cooling method. The gradient cooling method was to use a water bath to cool from 40°C to 30°C to 25°C, with each stage cooling to room temperature for 10 minutes, and the mixture was set aside.

[0062] (3) Preparation of suspension: The pretreated suspending stabilizer solution and beclomethasone dipropionate solution were mixed and subjected to dynamic cycle temperature control treatment (refrigeration at 8°C for 40 minutes, shaking at room temperature for 25 minutes, and three cycles), and then circulated four times using a high-pressure homogenizer (pressure of 100 MPa) to obtain a suspension.

[0063] (4) Filling and sealing: Use pressure filling method to fill the propellant to the full amount, ensure that the propellant and suspension are fully mixed, and seal.

[0064] Comparative Example 2 Beclomethasone dipropionate suspension for inhalation

[0065] formula:

[0066]

[0067] Preparation method:

[0068] (1) Pretreatment of beclomethasone dipropionate: Use air flow milling process, control the ambient humidity ≤30%, grind beclomethasone dipropionate to D90 <5μm, and immediately mix with an appropriate amount of propellant after grinding to avoid moisture absorption and agglomeration.

[0069] (2) Pretreatment of suspending stabilizer: leucine was pre-dispersed in part of the propellant after passing through a 200-mesh sieve, and ultrasonic-assisted dispersion was performed for 10 to 15 minutes and then set aside.

[0070] (3) Preparation of suspension: The pretreated suspending stabilizer solution and beclomethasone dipropionate solution were mixed and subjected to dynamic cycle temperature control treatment (refrigeration at 8°C for 40 minutes, shaking at room temperature for 25 minutes, and three cycles), and then circulated four times using a high-pressure homogenizer (pressure of 100 MPa) to obtain a suspension.

[0071] (4) Filling and sealing: Use pressure filling method to fill the propellant to the full amount, ensure that the propellant and suspension are fully mixed, and seal.

[0072] Comparative Example 3 Beclomethasone dipropionate suspension for inhalation

[0073] formula:

[0074]

[0075] Preparation method:

[0076] (1) Pretreatment of beclomethasone dipropionate: Use air flow milling process, control the ambient humidity ≤30%, grind beclomethasone dipropionate to D90 <5μm, and immediately mix with an appropriate amount of propellant after grinding to avoid moisture absorption and agglomeration.

[0077] (2) Pretreatment of suspending stabilizer: dissolve sodium dioctyl sulfosuccinate in an appropriate amount of propellant to form a homogeneous solution, and set aside; sieve leucine through a 200-mesh sieve and pre-disperse it in part of the propellant, and disperse it with ultrasound assistance for 10 to 15 minutes, and set aside; mix sodium alginate with an appropriate amount of propellant and heat it to 40°C to fully dissolve it, and cool it using a gradient cooling method. The gradient cooling method is to use a water bath to cool from 40°C to 30°C to 25°C, and cool it to room temperature for 10 minutes each stage, and set aside.

[0078] (3) Preparation of suspension: The pretreated suspending stabilizer solution and beclomethasone dipropionate solution were mixed and subjected to dynamic cycle temperature control treatment (refrigeration at 8°C for 40 minutes, shaking at room temperature for 25 minutes, and three cycles), and then circulated four times using a high-pressure homogenizer (pressure of 100 MPa) to obtain a suspension.

[0079] (4) Filling and sealing: Use pressure filling method to fill the propellant to the full amount, ensure that the propellant and suspension are fully mixed, and seal.

[0080] Comparative Example 4 Beclomethasone dipropionate suspension for inhalation

[0081] formula:

[0082]

[0083] Preparation method:

[0084] (1) Pretreatment of beclomethasone dipropionate: Use air flow milling process, control the ambient humidity ≤30%, grind beclomethasone dipropionate to D90 <5μm, and immediately mix with an appropriate amount of propellant after grinding to avoid moisture absorption and agglomeration.

[0085] (2) Pretreatment of suspending stabilizer: dissolve sodium dioctyl sulfosuccinate in an appropriate amount of propellant to form a homogeneous solution, and set aside; sieve leucine through a 200-mesh sieve and pre-disperse it in part of the propellant, and disperse it with ultrasound assistance for 10 to 15 minutes, and set aside; mix guar gum with an appropriate amount of propellant, heat it to 40°C to fully dissolve it, and directly cool it to room temperature (25°C) in a water bath, and set aside.

[0086] (3) Preparation of suspension: The pretreated suspending stabilizer solution and beclomethasone dipropionate solution were mixed and subjected to dynamic cycle temperature control treatment (refrigeration at 8°C for 40 minutes, shaking at room temperature for 25 minutes, and three cycles), and then circulated four times using a high-pressure homogenizer (pressure of 100 MPa) to obtain a suspension.

[0087] (4) Filling and sealing: Use pressure filling method to fill the propellant to the full amount, ensure that the propellant and suspension are fully mixed, and seal.

[0088] Single-factor experiment

[0089] The single-factor variable method was used to change only the presence or absence of the "dynamic cycle temperature control treatment" step or the process parameters, and other conditions (such as drug particle size, excipient ratio, homogenization pressure, etc.) remained consistent with Example 1.

[0090] Control group 1: The pretreated suspension stabilizer solution and beclomethasone dipropionate solution were mixed and circulated for 4 times using a high-pressure homogenizer (pressure of 100 MPa).

[0091] Control group 2: The pretreated suspension stabilizer solution and beclomethasone dipropionate solution were mixed, refrigerated at 8°C for 90 minutes, and then circulated for 4 times using a high-pressure homogenizer (pressure of 100 MPa).

[0092] Control group 3: The pretreated suspension stabilizer solution and beclomethasone dipropionate solution were mixed, shaken at room temperature for 35 minutes, and then circulated for 4 times using a high-pressure homogenizer (pressure of 100 MPa).

[0093] Control group 4: The pretreated suspension stabilizer solution and beclomethasone dipropionate solution were mixed and subjected to dynamic cycle temperature control treatment (15°C refrigeration for 40 minutes, room temperature shaking for 25 minutes, and three cycles), and then circulated for four times using a high-pressure homogenizer (pressure of 100 MPa).

[0094] Control group 5: The pretreated suspension stabilizer solution and beclomethasone dipropionate solution were mixed, refrigerated at 8°C for 40 minutes, shaken at room temperature for 25 minutes, and then circulated for 4 times using a high-pressure homogenizer (pressure of 100 MPa).

[0095] Physical stability of suspension

[0096] Sedimentation volume ratio (F value)

[0097] Place the suspension in a measuring cylinder, let it stand for 24 hours and 48 hours, and then measure the sediment height and total height to calculate the F value.

[0098] Table 1 Sedimentation volume ratio of each group of suspensions

[0099]

[0100] Table 1 shows that dynamic cyclic temperature control significantly improves suspension stability. The F value of Example 1 is significantly higher than that of Control 1, indicating that dynamic cyclic temperature control is a key step in maintaining suspension stability. The F value of Control 5, while higher than Controls 1-3, is still lower than that of Example 1, suggesting that cyclic operation has an additional effect on stability. Temperature and number of cycles influence stability. The F value of Control 4 is lower than that of Example 1, indicating that low temperature is more conducive to stability. The F values ​​of Controls 2 and 3 are both lower than those of Example 1, indicating that alternating refrigeration and shaking (rather than temperature control or shaking alone) is the key to the process. Single-factor experiments confirmed that the core reason for the difference in stability lies in the mechanism of action of dynamic cyclic temperature control: the low-temperature refrigeration stage reduces bubble formation in the suspension, promotes the formation of a tighter network structure of polymer excipients such as guar gum, enhances steric hindrance, and inhibits drug particle settling. The room-temperature shaking stage mechanically redisperses drug particles, preventing agglomeration, and promotes uniform mixing of the propellant and suspension, forming a more stable dispersion. Furthermore, through multiple cycles of "refrigeration-shaking," the particle dispersion state is continuously adjusted and the stabilizing effect of the excipients is enhanced, ultimately forming a more uniform, sedimentation-resistant suspension. Therefore, the dynamic cyclic temperature control treatment of the present invention significantly improves the physical stability of the suspension through the synergistic effects of low-temperature stabilization of the excipient structure, shaking to promote dispersion, and cyclic enhancement of uniformity. This experimental design, through single-factor control, clearly verifies the necessity of dynamic cyclic temperature control treatment and the influence of key parameters, providing data support for process optimization.

[0101] Chemical stability of suspension (accelerated test: 40℃ / 75%RH, 6 months)

[0102] The content of beclomethasone dipropionate was determined in accordance with the 2020 edition of the Chinese Pharmacopoeia by high performance liquid chromatography (General Chapter 0512). Internal standard solution: Take methyltestosterone, add mobile phase to dissolve and dilute to make a solution containing approximately 0.12 mg per 1 ml. Test solution: Take this product and accurately weigh it, place it in a 100 ml volumetric flask, add 74 ml of methanol to dissolve it, dilute it to the scale with water, and shake it well; accurately measure 10 ml of this solution and 5 ml of internal standard solution, place it in a 50 ml volumetric flask, dilute it to the scale with mobile phase, and shake it well. Reference solution: Take approximately 12.5 mg of beclomethasone dipropionate reference substance, accurately weigh it, place it in a 100 ml volumetric flask, add 74 ml of methanol to dissolve it, dilute it to the scale with water, and shake it well; accurately measure 10 ml of this solution and 5 ml of internal standard solution, place it in a 50 ml volumetric flask, dilute it to the scale with mobile phase, and shake it well. Chromatographic conditions: Octadecylsilane bonded silica gel as the filler; methanol-water (74:26) as the mobile phase; detection wavelength at 240 nm; injection volume of 20 μl. System suitability requirements: The number of theoretical plates calculated based on the beclomethasone dipropionate peak should be no less than 2500, and the resolution between the beclomethasone dipropionate peak and the internal standard peak should be greater than 4.0. Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatogram. Calculate the peak area according to the internal standard method.

[0103] Table 2 Beclomethasone dipropionate content

[0104]

[0105]

[0106] The data in Table 2 demonstrate that dynamic cyclic temperature control significantly improves the content stability of beclomethasone dipropionate. Dynamic cyclic temperature control significantly enhances the content stability of beclomethasone dipropionate suspensions through a triple mechanism: low temperature inhibits degradation, shaking promotes dispersion, and cyclic strengthening strengthens the structure. The combination of low temperature, circulation, and alternating refrigeration and shaking is key to achieving high stability; omitting any of these elements or adjusting key parameters (such as increasing the temperature or reducing the number of cycles) can lead to decreased stability.

[0107] Stability of Examples, Comparative Examples, and Commercially Available Beclomethasone Dipropionate Suspensions for Inhalation

[0108] Examples 1 to 3, Comparative Examples 1 to 4, and a commercially available beclomethasone dipropionate suspension for inhalation were stored at 40°C / 75% RH for 6 months. Samples were taken on day 0, at the end of the first month, at the end of the third month, and at the end of the sixth month to determine the beclomethasone dipropionate content and assess stability.

[0109] Table 3 Beclomethasone dipropionate content

[0110]

[0111] As can be seen from the data in Table 3, after being placed under accelerated conditions of 40°C / 75% RH for 6 months, the beclomethasone dipropionate content of Examples 1 to 3 remained above 99.9%, which was significantly better than that of Comparative Examples 1 to 4 and commercially available preparations. Examples 1 to 3 constructed a stable suspension system with strong steric hindrance and low surface energy by synergizing the sodium dioctyl sulfosuccinate-leucine-guar gum ternary suspension system with a gradient cooling dissolution process. The content decreased by less than 0.15% in 6 months, significantly improving the chemical stability of the beclomethasone dipropionate suspension for inhalation. The technical effect was comprehensively better than that of the comparative examples and commercially available preparations, providing a more reliable inhalation preparation option for clinical use.

[0112] The beclomethasone dipropionate suspensions for inhalation of Examples 1 to 3 and Comparative Examples 1 to 4 were placed at room temperature for 12 h, 24 h, and 48 h, and the sedimentation volume ratios (F values) were measured and calculated respectively.

[0113] Table 4 Sedimentation volume ratio (F value)

[0114]

[0115] The sedimentation volume ratio (F value) is an important indicator for measuring the physical stability of the suspension. The closer the F value is to 1, the slower the sedimentation rate of the drug particles in the suspension and the stronger the system stability. Combined with the data in Table 4, it can be seen that the overall F value of Examples 1 to 3 is higher and the stability decay rate is slower, indicating that the present invention significantly improves the physical stability of the inhaled beclomethasone dipropionate suspension through reasonable formulation design and process optimization. Its F value is significantly higher than that of the comparative example and commercially available preparations at each time point, and the system uniformity and anti-sedimentation ability are better, meeting the clinical demand for long-acting stable preparations.

Claims

1. A beclomethasone dipropionate suspension for inhalation, characterized in that: The beclomethasone dipropionate suspension for inhalation comprises, by mass fraction, 0.03-0.08% beclomethasone dipropionate, 1.4-2.75% suspending stabilizer, and the remainder being a propellant; the suspending stabilizer is a combination of sodium dioctyl sulfosuccinate, leucine, and guar gum.

2. The beclomethasone dipropionate suspension for inhalation according to claim 1, wherein The propellant is tetrafluoroethane and / or heptafluoropropane.

3. The beclomethasone dipropionate suspension for inhalation according to claim 1, wherein The components of the suspending stabilizer are calculated by mass fraction as follows: 0.2-0.5% sodium dioctyl sulfosuccinate, 0.8-1.5% leucine, and 0.4-0.75% guar gum.

4. The beclomethasone dipropionate suspension for inhalation according to claim 1, wherein The beclomethasone dipropionate D90 is less than 5 μm.

5. The beclomethasone dipropionate suspension for inhalation according to claim 1, wherein The beclomethasone dipropionate suspension for inhalation is calculated as follows by mass fraction: 0.05% beclomethasone dipropionate, 0.35% sodium dioctyl sulfosuccinate, 1.2% leucine, 0.6% guar gum, and 97.8% propellant.

6. A method for preparing the beclomethasone dipropionate suspension for inhalation according to claim 1, characterized in that: The method comprises the following steps: (1) Raw material pretreatment: air flow crushes beclomethasone dipropionate and immediately mixes with an appropriate amount of propellant; (2) Pretreatment of suspending agent: dissolve sodium dioctyl sulfosuccinate in part of the propellant; sieve leucine and ultrasonically disperse it in part of the propellant; dissolve guar gum in part of the propellant and heat to dissolve, then gradually cool to room temperature; (3) Preparation of suspension: The pretreatment solutions are mixed and then subjected to dynamic circulation temperature control, followed by high-pressure homogenization; (4) Filling and sealing: Pressure fill the propellant to the full amount, mix thoroughly and seal.

7. The method according to claim 6, characterized in that The gradient cooling is 35-45°C → 30°C → 25°C, with each stage lasting 10 minutes.

8. The method according to claim 6, characterized in that The dynamic cycle temperature control mixing comprises: refrigerating at 5-10° C. for 30-50 minutes, shaking at room temperature for 20-30 minutes, and repeating the cycle 2-4 times.

9. The method according to claim 6, characterized in that The pressure of the high-pressure homogenization is 80-100 MPa.

10. The method according to claim 6, characterized in that The method comprises the following steps: (1) Beclomethasone dipropionate pretreatment: Using a jet milling process, control the ambient humidity to ≤30%, and grind the beclomethasone dipropionate to a D90 <5 μm. Immediately after grinding, mix with an appropriate amount of propellant; (2) Pretreatment of suspending stabilizer: dissolve sodium dioctyl sulfosuccinate in an appropriate amount of propellant to form a homogeneous solution; leucine is pre-dispersed in a portion of the propellant after passing through a 200-mesh sieve, and ultrasonic-assisted dispersion is performed for 10 to 15 minutes; guar gum is mixed with an appropriate amount of propellant and heated to 35 to 45°C to dissolve, and then cooled to room temperature using a gradient cooling method of 35 to 45°C → 30°C → 25°C, with each stage lasting 10 minutes, for use; (3) Preparation of suspension: The pretreated suspending stabilizer solution and beclomethasone dipropionate solution were mixed, subjected to dynamic cycle temperature control treatment, refrigerated at 5-10°C for 30-50 minutes, shaken at room temperature for 20-30 minutes, and cycled 2-4 times, and then circulated using a high-pressure homogenizer for 3-5 times to obtain a suspension; (4) Filling and sealing: Use pressure filling method to fill the propellant to the full amount and seal.

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