A high-stability bumetanide tablet and a preparation method thereof

Abstract

The application discloses a high-stability solid preparation of bumetanide, which comprises the following components: bumetanide, an antioxidant, a pH regulator, a filling agent, a binder, a disintegrant, a surfactant, a lubricant and a flow aid. The high-stability solid preparation of bumetanide can solve the generation of N-nitroso-bumetanide impurities and other impurities during the production and storage of the preparation, and meanwhile, good dissolution behavior is maintained.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a highly stable bumetanide tablet and its preparation method. Background Technology

[0002] Bumetanib is a potent loop helix diuretic, and the most commonly available bumetanib tablets are currently 1 mg. Clinically, it is mainly used to treat edematous diseases, hypertension, acute kidney injury, and other conditions, and is especially suitable for patients with refractory edema who are unresponsive to furosemide.

[0003] During formulation manufacturing and storage, the secondary amine group in the bumetanide molecule may react with residual nitrites in excipients or nitrogen oxides in the environment to generate N-nitrosobumetanide impurities. This impurity belongs to the nitrosamine class of compounds, has clear genotoxicity, and is listed as a high-risk impurity by international drug regulatory agencies.

[0004] Given the well-established genotoxicity of nitrosamine impurities and the requirements for drug safety, drug regulatory agencies in various countries have established strict limit control systems for nitrosamine impurities. Control is implemented according to the Threshold for Toxicological Concern (TTC, 1.5 μg / day) proposed in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7(R1) guidelines. This standard fully considers the differences in tolerance among different populations, as well as factors such as the duration of drug use and route of administration, aiming to control the lifelong carcinogenic risk of patients taking this drug to below one in 100,000. In drug quality control, impurity limits are calculated based on the maximum daily intake of the drug. For the bumetanide preparation of this product, the maximum daily oral dose is 20 mg. The limit for nitrosamine impurities in the drug is calculated as follows: Control is implemented according to the Threshold for Toxicological Concern (TTC, 1.5 μg / day) proposed in the ICH M7(R1) guidelines:

[0005] Limit = 10 6 =75ppm, meaning the control limit for nitrosamine impurities in bumetanide is 75ppm.

[0006] The inventors discovered in their stability study of marketed bumetanide tablets that the N-nitrosobumetanide impurity exceeded the limit after 3 months of storage under accelerated test conditions of 40±2℃ and 75±5%RH.

[0007] The U.S. Food and Drug Administration (FDA) has studied the addition of antioxidants (such as ascorbic acid, caffeic acid, and ferulic acid) to bumetanide formulations to inhibit the formation of nitrosamine impurities. Experiments confirmed that ascorbic acid showed the strongest inhibitory effect; however, in practical applications, it can lead to the generation of unknown impurities in the formulation and introduce other impurities due to the degradation of the excipient itself, resulting in poor compatibility with bumetanide.

[0008] Patent CN120713883A discloses an oral solid dosage form of bumetanide with improved stability. Its core solution involves using ascorbate palmitate or propyl gallate to inhibit the formation of N-nitrosobumetanide impurities. This technical solution has the following limitations: Firstly, the control level of N-nitrosobumetanide impurities is limited. Data from the patent's examples show that N-nitrosobumetanide impurities were detected under accelerated 1-month conditions, and the impurity content continued to increase with prolonged storage time. Secondly, the excipients used in this patent differ from those in the original formulation, and no dissolution comparison data is provided, making it impossible to rule out dissolution risks.

[0009] The stability of bumetanide formulations has always been a technical challenge in the field. Under accelerated testing conditions of 40±2℃ and 75±5%RH, conventional bumetanide formulations show limited control of N-nitrosobumetanide impurities, and existing processes are complex and difficult to industrialize.

[0010] Therefore, developing a bumetanide drug composition that can effectively inhibit the formation of N-nitrosobumetanide impurities, has a simple process, and is suitable for industrial production has important clinical value and commercial significance. Summary of the Invention

[0011] This invention provides a bumetanide solid dosage form that can solve the problem of N-nitrosobumetanide impurities and other impurities being generated during the production and storage of the formulation, while maintaining good dissolution behavior.

[0012] In a first aspect, the present invention provides a solid pharmaceutical composition comprising or made from the following raw materials: bumetanide, antioxidant, pH adjuster, filler, binder, disintegrant, surfactant, lubricant, and flow aid.

[0013] In some embodiments, the antioxidant is anhydrous sodium sulfite.

[0014] In some embodiments, the pH adjuster is selected from one or more of sodium hydroxide and sodium bicarbonate, preferably sodium bicarbonate.

[0015] In some embodiments, the filler is selected from one or more of corn starch and lactose, preferably a combination of corn starch and lactose.

[0016] In some embodiments, the adhesive is selected from one or more of povidone K30, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, preferably povidone K30.

[0017] In some embodiments, the disintegrant is selected from one or more of agar, croscarmellose sodium, and croscarmellose, preferably agar.

[0018] In some embodiments, the surfactant is selected from one or more of Tween 80, Tween 20, and Tween 60, preferably Tween 80.

[0019] In some embodiments, the lubricant is selected from one or more of magnesium stearate and calcium stearate, preferably magnesium stearate.

[0020] In some embodiments, the flow aid is one or more of colloidal silica and talc, preferably a combination of colloidal silica and talc.

[0021] In some embodiments, the solid pharmaceutical composition comprises or is made from the following ingredients: bumetanide, anhydrous sodium sulfite, sodium bicarbonate, corn starch, lactose, povidone K30, agar, Tween 80, magnesium stearate, colloidal silica, and talc.

[0022] In some embodiments, the solid pharmaceutical composition comprises or is made from the following raw materials: 0.8-1.2 parts bumetanide, 0.6-1 parts anhydrous sodium sulfite, 1.5-2.5 parts sodium bicarbonate, 108-115 parts corn starch, 50-60 parts lactose, 4-6 parts povidone K30, 0.1-0.3 parts agar, 0.05-0.2 parts Tween 80, 1-3 parts magnesium stearate, 1-3 parts colloidal silica, and 1-3 parts talc.

[0023] In some embodiments, the solid pharmaceutical composition comprises or is made from the following raw materials: 1 part bumetanide, 0.6-0.8 parts anhydrous sodium sulfite, 1.6-2.4 parts sodium bicarbonate, 110.55-111.55 parts corn starch, 54 parts lactose, 5 parts povidone K30, 0.15 parts agar, 0.1 parts Tween 80, 2 parts magnesium stearate, 2 parts colloidal silica, and 2 parts talc.

[0024] In some embodiments, the solid pharmaceutical composition comprises or is made from the following ingredients: 1 part bumetanide, 0.8 parts anhydrous sodium sulfite, 1.6 parts sodium bicarbonate, 111.35 parts corn starch, 54 parts lactose, 5 parts povidone K30, 0.15 parts agar, 0.1 parts Tween 80, 2 parts magnesium stearate, 2 parts colloidal silica, and 2 parts talc.

[0025] In some embodiments, the solid pharmaceutical composition comprises or is made from the following ingredients: 1 part bumetanide, 0.6 parts anhydrous sodium sulfite, 2 parts sodium bicarbonate, 111.15 parts corn starch, 54 parts lactose, 5 parts povidone K30, 0.15 parts agar, 0.1 parts Tween 80, 2 parts magnesium stearate, 2 parts colloidal silica, and 2 parts talc.

[0026] In some embodiments, the solid pharmaceutical composition comprises or is made from the following ingredients: 1 part bumetanide, 0.8 parts anhydrous sodium sulfite, 2.4 parts sodium bicarbonate, 110.55 parts corn starch, 54 parts lactose, 5 parts povidone K30, 0.15 parts agar, 0.1 parts Tween 80, 2 parts magnesium stearate, 2 parts colloidal silica, and 2 parts talc.

[0027] In some embodiments, the solid pharmaceutical composition comprises or is made from the following ingredients: 1 part bumetanide, 0.6 parts anhydrous sodium sulfite, 2 parts sodium bicarbonate, 111.55 parts corn starch, 54 parts lactose, 5 parts povidone K30, 0.15 parts agar, 0.1 parts Tween 80, 2 parts magnesium stearate, 2 parts colloidal silica, and 2 parts talc.

[0028] In some embodiments, the solid pharmaceutical composition comprises or is made from the following ingredients: 1 part bumetanide, 0.6 parts anhydrous sodium sulfite, 2 parts sodium bicarbonate, 111.15 parts corn starch, 54 parts lactose, 5 parts povidone K30, 0.15 parts agar, 0.1 parts Tween 80, 2 parts magnesium stearate, 2 parts colloidal silica, and 2 parts talc.

[0029] In some embodiments, the dosage form of the solid pharmaceutical composition is a tablet.

[0030] In a second aspect, the present invention provides a method for preparing the solid pharmaceutical composition described in the first aspect, comprising the following steps:

[0031] S1: Add agar to purified water and heat to 90±5℃. After the agar gels, cool down to 40±5℃, add povidone K30, stir to dissolve, and then add Tween 80 to prepare the adhesive solution.

[0032] S2: Bumetanide raw material is pulverized by air jet milling until the D90 particle size is ≤35μm to obtain pulverized material;

[0033] S3: Add bumetanide powder, anhydrous sodium sulfite, sodium bicarbonate, lactose, corn starch and binder solution to a wet granulation mixer, set the stirring speed to 100 rpm, the chopping speed to 1200 rpm, and the granulation time to 5 min.

[0034] S4: After the wet granules are sized through an 18-mesh sieve, they are dried in a fluidized bed with an inlet air temperature of 55±5℃ and a material temperature of 40±5℃. The moisture content of the dried granules is ≤3%, thus obtaining dry granules.

[0035] S5: After granulating the dry granules, add talc, magnesium stearate and colloidal silica and mix evenly to obtain intermediate granules;

[0036] S6: Compress the intermediate particles into tablets using a rotary tablet press, controlling the tablet weight to 180mg and the hardness to 4-6kg.

[0037] Thirdly, the present invention provides the use of the solid pharmaceutical composition described in the first aspect or the solid pharmaceutical composition prepared according to the preparation method described in the second aspect in the preparation of a medicament for treating a disease selected from edematous diseases, hypertension, or acute kidney injury.

[0038] Beneficial effects:

[0039] The pharmaceutical composition of the present invention, after being placed under accelerated testing conditions of 40±2℃ and 75±5%RH for 6 months, showed no N-nitrosobumetanide impurities and maintained good dissolution behavior.

[0040] This invention uses anhydrous sodium sulfite as an antioxidant and sodium bicarbonate as a pH adjuster. The preparation method employs air jet milling to control the raw material particle size D90≤35μm, combined with an agar-povidone-Tween 80 binding system for wet granulation. This effectively solves the technical problem of N-nitrosobumetanide impurities and other impurities in bumetanide solid dosage forms during production and storage, while maintaining good dissolution behavior and significantly improving the stability and safety of bumetanide formulations. Attached Figure Description

[0041] Figure 1 Results of total impurity detection in the examples and comparative examples.

[0042] Figure 2 Results of the detection of N-nitrosobumetanide impurities in the examples and comparative examples. Detailed Implementation

[0043] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0044] Example 1

[0045] The prescription for bumetanide tablets is shown in Table 1.

[0046] Table 1

[0047]

[0048] Preparation process:

[0049] S1: Add agar to purified water and heat to 90±5℃. After the agar gels, cool down to 40±5℃, add povidone, stir to dissolve, and then add Tween 80 to prepare the adhesive solution.

[0050] S2: Bumetanide raw material is pulverized by air jet milling until the D90 particle size is ≤35μm to obtain pulverized material;

[0051] S3: Add bumetanide powder, anhydrous sodium sulfite, sodium bicarbonate, lactose, corn starch and binder solution to a wet granulation mixer, set the stirring speed to 100 rpm, the chopping speed to 1200 rpm, and the granulation time to 5 min.

[0052] S4: After the wet granules are sized through an 18-mesh sieve, they are dried in a fluidized bed with an inlet air temperature of 55±5℃ and a material temperature of 40±5℃. The moisture content of the dried granules is ≤3%, thus obtaining dry granules.

[0053] S5: After granulating the dry granules, add talc, magnesium stearate and colloidal silica and mix evenly to obtain intermediate granules;

[0054] S6: Compress the intermediate particles into tablets using a rotary tablet press, controlling the tablet weight to 180mg and the hardness to 4-6kg.

[0055] Example 2

[0056] The prescription for bumetanide tablets is shown in Table 2.

[0057] Table 2

[0058]

[0059] Preparation process:

[0060] S1: Add agar to purified water and heat to 90±5℃. After the agar gels, cool down to 40±5℃, add povidone, stir to dissolve, and then add Tween 80 to prepare the adhesive solution.

[0061] S2: Bumetanide raw material is pulverized by air jet milling until the D90 particle size is ≤35μm to obtain pulverized material;

[0062] S3: Add bumetanide powder, anhydrous sodium sulfite, sodium bicarbonate, lactose, corn starch and binder solution to a wet granulation mixer, set the stirring speed to 100 rpm, the chopping speed to 1200 rpm, and the granulation time to 5 min.

[0063] S4: After the wet granules are sized through an 18-mesh sieve, they are dried in a fluidized bed with an inlet air temperature of 55±5℃ and a material temperature of 40±5℃. The moisture content of the dried granules is ≤3%, thus obtaining dry granules.

[0064] S5: After granulating the dry granules, add talc, magnesium stearate and colloidal silica and mix evenly to obtain intermediate granules;

[0065] S6: Compress the intermediate particles into tablets using a rotary tablet press, controlling the tablet weight to 180mg and the hardness to 4-6kg.

[0066] Example 3

[0067] The prescription for bumetanide tablets is shown in Table 3.

[0068] Table 3

[0069]

[0070] Preparation process:

[0071] S1: Add agar to purified water and heat to 90±5℃. After the agar gels, cool down to 40±5℃, add povidone, stir to dissolve, and then add Tween 80 to prepare the adhesive solution.

[0072] S2: Bumetanide raw material is pulverized by air jet milling until the D90 particle size is ≤35μm to obtain pulverized material;

[0073] S3: Add bumetanide powder, anhydrous sodium sulfite, sodium bicarbonate, lactose, corn starch and binder solution to a wet granulation mixer, set the stirring speed to 100 rpm, the chopping speed to 1200 rpm, and the granulation time to 5 min.

[0074] S4: After the wet granules are sized through an 18-mesh sieve, they are dried in a fluidized bed with an inlet air temperature of 55±5℃ and a material temperature of 40±5℃. The moisture content of the dried granules is ≤3%, thus obtaining dry granules.

[0075] S5: After granulating the dry granules, add talc, magnesium stearate and colloidal silica and mix evenly to obtain intermediate granules;

[0076] S6: Compress the intermediate particles into tablets using a rotary tablet press, controlling the tablet weight to 180mg and the hardness to 4-6kg.

[0077] Example 4

[0078] The prescription for bumetanide tablets is shown in Table 4.

[0079] Table 4

[0080]

[0081] Preparation process:

[0082] S1: Add agar to purified water and heat to 90±5℃. After the agar gels, cool down to 40±5℃, add povidone, stir to dissolve, and then add Tween 80 to prepare the adhesive solution.

[0083] S2: Bumetanide raw material is pulverized by air jet milling until the D90 particle size is ≤20μm to obtain pulverized material;

[0084] S3: Add bumetanide powder, anhydrous sodium sulfite, sodium bicarbonate, lactose, corn starch and binder solution to a wet granulation mixer, set the stirring speed to 100 rpm, the chopping speed to 1200 rpm, and the granulation time to 5 min.

[0085] S4: After the wet granules are sized through an 18-mesh sieve, they are dried in a fluidized bed with an inlet air temperature of 55±5℃ and a material temperature of 40±5℃. The moisture content of the dried granules is ≤3%, thus obtaining dry granules.

[0086] S5: After granulating the dry granules, add talc, magnesium stearate and colloidal silica and mix evenly to obtain intermediate granules;

[0087] S6: Compress the intermediate particles into tablets using a rotary tablet press, controlling the tablet weight to 180mg and the hardness to 4-6kg.

[0088] Example 5

[0089] The prescription for bumetanide tablets is shown in Table 5.

[0090] Table 5

[0091]

[0092] Preparation process:

[0093] S1: Add agar to purified water and heat to 90±5℃. After the agar gels, cool down to 40±5℃, add povidone and stir to dissolve, add anhydrous sodium sulfite and stir to dissolve, then add Tween 80 to prepare the adhesive solution.

[0094] S2: Bumetanide raw material is pulverized by air jet milling until the D90 particle size is ≤35μm to obtain pulverized material;

[0095] S3: Add bumetanide powder, sodium bicarbonate, lactose, corn starch and binder solution to a wet granulation mixer, set the stirring speed to 100 rpm, the chopping speed to 1200 rpm, and the granulation time to 5 min;

[0096] S4: After the wet granules are sized through an 18-mesh sieve, they are dried in a fluidized bed with an inlet air temperature of 55±5℃ and a material temperature of 40±5℃. The moisture content of the dried granules is ≤3%, thus obtaining dry granules.

[0097] S5: After granulating the dry granules, add talc, magnesium stearate and colloidal silica and mix evenly to obtain intermediate granules;

[0098] S6: Compress the intermediate particles into tablets using a rotary tablet press, controlling the tablet weight to 180mg and the hardness to 4-6kg.

[0099] Comparative Example

[0100] Examples of bumetanide tablets (components 1-4) are shown in Table 6.

[0101] Table 6

[0102]

[0103] Preparation process:

[0104] S1: Add agar to purified water and heat to 90±5℃. After the agar gels, cool down to 40±5℃, add povidone, stir to dissolve, and then add Tween 80 to prepare the adhesive solution.

[0105] S2: Bumetanide raw material is pulverized by air jet milling until the D90 particle size is ≤35μm to obtain pulverized material;

[0106] S3: Add bumetanide powder, antioxidant and / or pH adjuster, lactose, corn starch and binder solution to a wet granulation mixer, set the stirring speed to 100 rpm, the chopping speed to 1200 rpm, and the granulation time to 5 min;

[0107] S4: After the wet granules are sized through an 18-mesh sieve, they are dried in a fluidized bed with an inlet air temperature of 55±5℃ and a material temperature of 40±5℃. The moisture content of the dried granules is ≤3%, thus obtaining dry granules.

[0108] S5: After granulating the dry granules, add talc, magnesium stearate and colloidal silica and mix evenly to obtain intermediate granules;

[0109] S6: Compress the intermediate particles into tablets using a rotary tablet press, controlling the tablet weight to 180mg and the hardness to 4-6kg.

[0110] Test case

[0111] The above-described examples, comparative examples, and original bumetanide tablets were placed under conditions of (40±2℃ / 75±5%RH) for 6 months. Samples were taken at different time points to test the appearance, related substances, N-nitrosobumetanide impurities, and dissolution rate.

[0112] The method for detecting N-nitrosobumetanide impurities is as follows: Determination is performed by liquid chromatography-triple quadrupole mass spectrometry (LC-MS / MS). The solvent is methanol-water (containing 0.1% formic acid). For the test solution, take 20 tablets of this product, grind them finely, accurately weigh an appropriate amount (approximately equivalent to 50 mg of bumetanide), place it in a 50 ml volumetric flask, add an appropriate amount of methanol, sonicate to dissolve the bumetanide, dilute to the mark with solvent, shake well, filter, and collect the filtrate. For the reference solution, accurately weigh an appropriate amount of N-nitrosobumetanide reference standard, dissolve it in methanol, and quantitatively dilute to prepare a solution containing approximately 0.05 μg per ml. For the system suitability solution, take appropriate amounts of N-nitrosobumetanide reference standard and bumetanide reference standard, dissolve them in methanol, and dilute to prepare a mixed solution containing approximately 0.1 μg of each per ml. Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Agilent ZORBAX Eclipse Plus C18, 4.6 mm × 150 mm, 3.5 μm or equivalent column). 0.1% formic acid solution was used as mobile phase A and methanol was used as mobile phase B. Gradient elution was performed according to the table below. The flow rate was 1.0 mL per minute, the column temperature was 35 °C, and the injection volume was 50 μL.

[0113] Table 7

[0114]

[0115] Related substances detection method: Determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512). Solvent: Acetonitrile-water (4:6); Test solution: Take 10 tablets of this product, place them in a 20ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve bumetanide, dilute to the mark with solvent, shake well, filter, and collect the filtrate. For the reference solution, accurately measure 1 ml of the test solution and place it in a 100 ml volumetric flask. Dilute to the mark with solvent and shake well. For the system suitability solution, take appropriate amounts of bumetanide reference standard and each impurity reference standard, dissolve and dilute with solvent to prepare a mixed solution containing approximately 1 μg of each in 1 ml. For the chromatographic conditions, use octadecylsilane-bonded silica gel as the stationary phase (Waters XBridge C18, 4.6 mm × 250 mm, 5 μm or equivalent column), with 0.05% phosphoric acid solution as mobile phase A and acetonitrile as mobile phase B. Perform gradient elution according to the table below, with a flow rate of 1.0 ml per minute; column temperature of 30°C; detection wavelength of 254 nm; and injection volume of 10 μl.

[0116] Table 8

[0117]

[0118] Dissolution testing method: The dissolution and release rate determination was performed according to the method of determination of dissolution and release rate (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0931, Method I) and high performance liquid chromatography (General Chapter 0512). The dissolution medium was 900 ml of phosphate buffer (pH 7.8–8.0), using the basket method, a rotation speed of 100 rpm, and a temperature of 37℃ ± 0.5℃. The procedure was followed, and samples were taken after 30 minutes. 25 ml of the dissolution solution was collected from the test solution, filtered, and the filtrate was collected. For the reference solution, accurately weigh bumetanide reference standard, dissolve and quantitatively dilute with dissolution medium to prepare a solution containing approximately 1.1 μg per ml; for the system suitability solution, dissolve and dilute an appropriate amount of bumetanide reference standard with dissolution medium to prepare a solution containing approximately 1.1 μg per ml; for the chromatographic conditions, use octadecylsilane-bonded silica gel as the stationary phase (e.g., YMC-Pack ODS-A, 4.6 mm × 150 mm, 5 μm or equivalent column), with methanol-0.1% trifluoroacetic acid solution (58:42) as the mobile phase, a flow rate of 1.0 ml per minute; a detection wavelength of 344 nm; a column temperature of room temperature; and an injection volume of 100 μl.

[0119] The appearance and related substances test results of bumetanide tablets under accelerated testing conditions of 40±2℃ and 75±5%RH are shown in Table 9.

[0120] Table 9

[0121] The results of N-nitrosobumetane impurity testing under accelerated test conditions of 40±2℃ and 75±5%RH are shown in Table 10.

[0122] Table 10

[0123]

[0124] The dissolution test results under accelerated test conditions of 40±2℃ and 75±5%RH are shown in Table 11.

[0125] Table 11

[0126]

[0127] As shown in Table 9, after 6 months of accelerated testing at 40℃±2℃ and 75%±5%RH: the reference formulation (Burinex) ® The total impurity content increased over time and was generally higher than in the embodiments of the present invention. This result indicates that the combined use of anhydrous sodium sulfite and sodium bicarbonate in the present invention has an inhibitory effect on the formation of related substances.

[0128] As shown in Table 9, the sample samples from the examples, after being placed under accelerated testing conditions of 40℃±2℃ and 75%±5%RH for 6 months, all appeared as off-white flakes, while Comparative Example 3 (ascorbic acid group) showed yellowing. This result indicates that the formulation of the present invention has a greater advantage in terms of appearance stability.

[0129] As shown in Table 10, N-nitrosobumetanide impurities were detected in the reference formulation and all comparative examples at 0°C, while those in Examples 1-5 were not detected within 6 months under accelerated conditions of 40°C ± 2°C and 75% ± 5% RH. These results indicate that the combined use of anhydrous sodium sulfite and sodium bicarbonate in this invention can effectively inhibit the formation of N-nitrosobumetanide impurities.

[0130] As shown in Table 11, the samples from the examples, after being placed under accelerated conditions of 40℃±2℃ and 75%±5%RH for 6 months, all met the quality standard requirements for dissolution. This result demonstrates that the formulation and preparation method of this invention have advantages in terms of dissolution behavior stability.

[0131] In summary, the bumetanide oral solid dosage form provided by this invention, through the synergistic effect of anhydrous sodium sulfite and sodium bicarbonate, can effectively control the formation of N-nitrosobumetanide impurities and other related substances, while maintaining the good appearance and dissolution behavior of the formulation, and significantly improving the stability and safety of the bumetanide formulation.

Claims

1. A solid pharmaceutical composition, characterized in that, The solid pharmaceutical composition is made from the following raw materials: 0.8-1.2 parts bumetanide, 0.6-1 parts anhydrous sodium sulfite, 1.5-2.5 parts sodium bicarbonate, 108-115 parts corn starch, 50-60 parts lactose, 4-6 parts povidone K30, 0.1-0.3 parts agar, 0.05-0.2 parts Tween 80, 1-3 parts magnesium stearate, 1-3 parts colloidal silica, and 1-3 parts talc.

2. The solid pharmaceutical composition according to claim 1, characterized in that, The solid pharmaceutical composition is selected from one of the following: (1) The solid pharmaceutical composition is made from the following raw materials: 1 part bumetanide, 0.8 parts anhydrous sodium sulfite, 1.6 parts sodium bicarbonate, 111.35 parts corn starch, 54 parts lactose, 5 parts povidone K30, 0.15 parts agar, 0.1 parts Tween 80, 2 parts magnesium stearate, 2 parts colloidal silica, and 2 parts talc. (2) The solid pharmaceutical composition is made from the following raw materials: 1 part bumetanide, 0.6 parts anhydrous sodium sulfite, 2 parts sodium bicarbonate, 111.15 parts corn starch, 54 parts lactose, 5 parts povidone K30, 0.15 parts agar, 0.1 parts Tween 80, 2 parts magnesium stearate, 2 parts colloidal silica, and 2 parts talc. (3) The solid pharmaceutical composition is made from the following raw materials: 1 part bumetanide, 0.8 parts anhydrous sodium sulfite, 2.4 parts sodium bicarbonate, 110.55 parts corn starch, 54 parts lactose, 5 parts povidone K30, 0.15 parts agar, 0.1 parts Tween 80, 2 parts magnesium stearate, 2 parts colloidal silica, and 2 parts talc.

3. The solid pharmaceutical composition according to claim 1 or 2, characterized in that, The dosage form of the solid pharmaceutical composition is a tablet.

4. A method for preparing the solid pharmaceutical composition according to claim 3, comprising the following steps: S1: Add agar to purified water and heat to 90±5℃. After the agar gels, cool down to 40±5℃, add povidone K30, stir to dissolve, and then add Tween 80 to prepare the adhesive solution. S2: Bumetanide raw material is pulverized by air jet milling until the D90 particle size is ≤35μm to obtain pulverized material; S3: Add bumetanide powder, anhydrous sodium sulfite, sodium bicarbonate, lactose, corn starch and binder solution to a wet granulation mixer, set the stirring speed to 100 rpm, the chopping speed to 1200 rpm, and the granulation time to 5 min. S4: After the wet granules are sized through an 18-mesh sieve, they are dried in a fluidized bed with an inlet air temperature of 55±5℃ and a material temperature of 40±5℃. The moisture content of the dried granules is ≤3%, thus obtaining dry granules. S5: After granulating the dry granules, add talc, magnesium stearate and colloidal silica and mix evenly to obtain intermediate granules; S6: Compress the intermediate particles into tablets using a rotary tablet press, controlling the tablet weight to 180mg and the hardness to 4-6kg.

5. The use of the solid pharmaceutical composition according to claim 3 or the solid pharmaceutical composition prepared by the method according to claim 4 in the preparation of a medicament for treating a disease selected from hypertension or acute kidney injury.

Images