Bumetanib oral solid preparation with improved stability and preparation method of bumetanib oral solid preparation

Abstract

The present invention provides a pharmaceutical composition, the composition comprises a therapeutically effective amount of bumetanib, one or more specific antioxidants and other necessary one or more pharmaceutically acceptable pharmaceutic adjuvants, and the specific antioxidants are selected from one or more of fat-soluble vitamin C derivatives or phenolic antioxidants. In addition, the invention also discloses a method for improving the stability of the bumetanib pharmaceutical composition. According to the technical scheme, the problems of generation and growth of N-nitroso bumetanib and other related substances in the production and storage process of the bumetanib solid preparation are effectively solved, and the drug stability and the medication safety are remarkably improved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a pharmaceutical composition and method for effectively solving the problem of the generation and growth of N-nitrosobumetanide and other related substances during the production and storage of a bumetanide drug combination. Background Art

[0002] Bumetanide, whose chemical name is 3-butylamino-4-phenoxy-5-sulfonylbenzoic acid, has a chemical structure as shown in formula (A):

[0003] Bumetanide, an important derivative of m-aminobenzenesulfonamide, reaches peak plasma concentration within 1 to 2 hours after oral administration. Primarily metabolized in the liver, it acts by inhibiting active chloride transport and passive sodium reabsorption in the loop of Henle, thereby exerting a significant diuretic effect. It is a highly effective diuretic widely used in clinical practice.

[0004] Due to the presence of a secondary amine group in the molecular structure of bumetanide, it is very easy to chemically react with nitrites contained in pharmaceutical excipients during the production process and storage of pharmaceutical preparations, thereby generating N-nitrosamine bumetanide impurities. This impurity is a potential carcinogen, which significantly increases the potential safety risks during patient use. The generation mechanism of N-nitrosamine bumetanide impurities is shown in Formula (B):

[0005] Nitrosamines are characterized by a direct bond between a nitroso group and an amine group. During metabolism in the body, they are converted into alkyldiazonium ions. These ions specifically act on the nitrogen and oxygen atoms contained in bases such as guanine, cytosine, and thymine in DNA molecules, inducing DNA alkylation modifications, leading to base pair mismatches and gene mutations, and thus posing a potential carcinogenic risk to organisms.

[0006] From the perspective of impurity control, nitrosamine impurities have high chemical stability and are difficult to effectively remove using conventional treatment methods; and as the storage period of drugs increases, their content in drugs may show a trend of continuous growth.

[0007] In view of the clear genotoxicity of nitrosamine impurities and the safety requirements of drugs, drug regulatory agencies in various countries have established a strict limit control system for nitrosamine impurities. According to the relevant guidelines issued by the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), based on the toxicological concern threshold method, the acceptable daily intake of nitrosamine impurities is 1.5μg / day. This standard fully considers the tolerance differences of different populations, as well as factors such as the drug use cycle and administration route. It aims to control the carcinogenic risk of patients taking the drug for life to less than one in 100,000. In drug quality control, the impurity limit is calculated based on the maximum daily intake of the drug. The maximum daily oral intake of bumetanide preparation of this product is 20mg, so the limit of nitrosamine impurities in the drug is calculated = 1.5μg / day ÷ 20mg × 10 6 , it can be concluded that the control limit of nitrosamine impurities in bumetanide drugs is 75ppm.

[0008] Currently, attempts to inhibit the production of nitrosamine impurities face numerous challenges. For example, some literature reports suggest reducing the risk of nitrosamine impurities by adjusting the pH of the formulation with alkaline excipients or by adding antioxidants (caffeic acid, ferulic acid, and ascorbic acid). However, these methods can lead to the production of unknown impurities in the formulation, as well as other unknown impurities introduced through the degradation of these excipients. These methods cannot effectively control the growth of impurities in the formulation under accelerated and long-term testing conditions, and they exhibit poor compatibility with bumetanide.

[0009] Patent CN 118680914 A discloses a bumetanide composition and preparation method thereof. The composition employs the addition of stabilizers magnesium oxide and meglumine to the formulation and undergoes multiple processes, including airflow milling, wet granulation, and boiling granulation. However, this technical solution has certain limitations. On the one hand, the complex formulation system and multi-step preparation process increase the technical difficulty and cost of industrialized production, making it difficult to meet the efficiency requirements of large-scale industrial production. On the other hand, the composition and process have no significant effect on the control of related substances and specific impurities (such as Maillard impurities), and cannot effectively guarantee the quality stability of the drug.

[0010] Given the shortcomings of existing technologies in controlling N-nitrosobumetanide impurities and bumetanide-related substances, there is an urgent need to develop an efficient and feasible method that can effectively inhibit the production of the above-mentioned impurities, thereby improving the quality of bumetanide preparations and ensuring clinical drug safety. Summary of the Invention

[0011] The present inventors have developed a bumetanide solid preparation that can effectively inhibit the formation of N-nitrosamine bumetanide impurities and other related substances during preparation production and storage.

[0012] Specifically, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of bumetanide, one or more antioxidants, and one or more pharmaceutically acceptable excipients. The antioxidants are selected from one or more of fat-soluble vitamin C derivatives and phenolic antioxidants. Fat-soluble vitamin C derivatives, due to their unique lipid solubility, can be uniformly dispersed in the material system, effectively capturing free radicals and blocking the impurity generation pathway initiated by oxidation reactions. Phenolic antioxidants, by donating hydrogen atoms, quench free radicals and inhibit the oxidative chain reaction. The rational selection of these antioxidants provides a strong guarantee for impurity suppression at the molecular mechanism level.

[0013] In a preferred embodiment of the present invention, the fat-soluble vitamin C derivative is ascorbyl palmitate; preferably, the mass of the ascorbyl palmitate accounts for 0.1%-5% of the total mass of the pharmaceutical composition.

[0014] In a preferred embodiment of the present invention, the phenolic antioxidant is propyl gallate; preferably, the mass of the propyl gallate accounts for 0.5%-3% of the total mass of the pharmaceutical composition.

[0015] In a preferred embodiment of the present invention, the pharmaceutical excipients include one or more of a filler, a disintegrant, a binder, a glidant and a lubricant.

[0016] In a preferred embodiment of the present invention, the filler is selected from one or more of starch and its derivatives, lactose, microcrystalline cellulose, and mannitol; preferably, the filler comprises lactose or starch; more preferably, the mass of the filler accounts for 70-95% of the total mass of the pharmaceutical composition.

[0017] In a preferred embodiment of the present invention, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose. More preferably, the mass of the disintegrant accounts for 1-10% of the total mass of the pharmaceutical composition.

[0018] In a preferred embodiment of the present invention, the binder is selected from one or more of povidone, hypromellose, and hydroxypropyl cellulose. More preferably, the binder accounts for 0.1-5% of the total mass of the pharmaceutical composition.

[0019] In a preferred embodiment of the present invention, the glidant is one or more of silicon dioxide, talc, hydrogenated vegetable oil, calcium silicate and magnesium silicate. Preferably, the glidant is silicon dioxide; more preferably, the mass of the glidant accounts for 0.1-5% of the total mass of the pharmaceutical composition.

[0020] In a preferred embodiment of the present invention, the lubricant is selected from one or more of magnesium stearate, talc, and magnesium stearate fumarate. More preferably, the mass of the lubricant accounts for 0.05-3% of the total mass of the pharmaceutical composition.

[0021] In a preferred embodiment of the present invention, after the pharmaceutical composition is exposed to 40°C / 75% RH for 2 months, the amount of the N-nitrosamine bumetanide impurity is less than 75 ppm, wherein the amount of the N-nitrosamine bumetanide impurity is determined by high performance liquid chromatography (HPLC).

[0022] Preferably, the amount of the N-nitrosamine bumetanide impurity is less than 75 ppm after exposing the pharmaceutical composition to 40°C / 75% RH for a period of 6 months.

[0023] More preferably, the amount of the N-nitrosamine bumetanide impurity in the pharmaceutical composition is less than 75 ppm during the drug's shelf life. The shelf life of a drug generally refers to the shelf life of the drug in the form sold to consumers, during which the drug is suitable for patient use. The term "shelf life" also refers to the period during which a drug can maintain its quality, safety, and effectiveness under specified storage conditions. During this period, the drug's ingredients, content, properties, etc. meet the requirements of national drug standards or drug registration standards and can be used safely and effectively. The drug's shelf life can be greater than 3 months, 6 months, 12 months, 18 months, 24 months, and preferably 36 months. Specified storage conditions for drugs include "a cool, dry, dark place, at a temperature not exceeding 25°C" or "light-shielded, airtight storage."

[0024] In a preferred embodiment of the present invention, the pharmaceutical composition is a solid preparation or a liquid preparation; preferably, the solid preparation is a powder, granules, tablets or capsules.

[0025] Specifically, in a preferred embodiment of the present invention, the composition comprises a therapeutically effective amount of bumetanide, one or more antioxidants, and one or more pharmaceutically acceptable excipients, wherein the antioxidant is selected from one or more of ascorbyl palmitate and propyl gallate. Preferably, the mass of bumetanide accounts for 0.1-2% of the total mass of the pharmaceutical composition.

[0026] In a second aspect, the present invention provides a method for improving the stability of a bumetanide pharmaceutical composition, the method comprising mixing bumetanide with one or more antioxidants, wherein the antioxidants are selected from one or more of a fat-soluble vitamin C derivative or a phenolic antioxidant.

[0027] In a preferred embodiment of the present invention, the fat-soluble vitamin C derivative is ascorbyl palmitate.

[0028] In a preferred embodiment of the present invention, the phenolic antioxidant is propyl gallate.

[0029] In a preferred embodiment of the present invention, the weight of the antioxidant accounts for 0.5%-3% of the total weight of the pharmaceutical composition.

[0030] In a preferred embodiment of the present invention, the method comprises mixing bumetanide with one or more antioxidants and a pharmaceutical excipient; the pharmaceutical excipient comprises one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0031] In a preferred embodiment of the present invention, the filler is selected from one or more of starch and its derivatives, lactose, microcrystalline cellulose, and mannitol; more preferably, the filler includes lactose or starch; In a preferred embodiment of the present invention, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose.

[0032] In a preferred embodiment of the present invention, the binder is selected from one or more of povidone, hypromellose, and hydroxypropyl cellulose.

[0033] In a preferred embodiment of the present invention, after the pharmaceutical composition prepared by the aforementioned method is exposed to 40°C / 75% RH for 2 months, the amount of the N-nitrosamine bumetanide impurity is less than 75 ppm; the amount of the N-nitrosamine bumetanide impurity is determined by high-performance liquid chromatography (HPLC). Preferably, after the pharmaceutical composition prepared by the aforementioned method is exposed to 40°C / 75% RH for 2 months, the amount of the Maillard impurity is less than 0.5%. The amount of the Maillard impurity is determined by high-performance liquid chromatography (HPLC) and calculated by area normalization.

[0034] In a preferred embodiment of the present invention, Maillard impurities refer to impurities generated by the reaction of bumetanide with pharmaceutical excipients, and the specific structure is shown in Formula (C):

[0035] In a preferred embodiment of the present invention, after the pharmaceutical composition prepared by the above method is exposed to 40°C / 75% RH for 6 months, the amount of the N-nitrosamine bumetanide impurity is less than 75 ppm; preferably, after the pharmaceutical composition prepared by the above method is exposed to 40°C / 75% RH for 6 months, the amount of the Maillard impurity is less than 0.5%.

[0036] In a preferred embodiment of the present invention, the amount of the N-nitrosamine bumetanide impurity in the pharmaceutical composition prepared by the aforementioned method is less than 75 ppm during the shelf life of the drug; preferably, the amount of the Maillard impurity in the pharmaceutical composition prepared by the aforementioned method is less than 0.5% during the shelf life of the drug.

[0037] In a third aspect, the present invention provides a pharmaceutical composition prepared according to the method of the second aspect, wherein the amount of the N-nitrosamine bumetanide impurity in the pharmaceutical composition is less than 75 ppm after exposure to 40°C / 75% RH for 2 months. Preferably, the amount of the Maillard impurity in the pharmaceutical composition is less than 0.5% after exposure to 40°C / 75% RH for 2 months.

[0038] In a preferred embodiment of the present invention, the present invention provides a pharmaceutical composition prepared according to the method of the second aspect, wherein the amount of the N-nitrosamine bumetanide impurity in the pharmaceutical composition is less than 75 ppm after exposure to 40°C / 75% RH for 6 months. Preferably, the amount of the Maillard impurity in the pharmaceutical composition is less than 0.5% after exposure to 40°C / 75% RH for 6 months.

[0039] In a preferred embodiment of the present invention, the present invention provides a pharmaceutical composition prepared according to the method of the second aspect, wherein the amount of the N-nitrosamine bumetanide impurity in the pharmaceutical composition is less than 75 ppm within the shelf life of the pharmaceutical composition. The amount of the N-nitrosamine bumetanide impurity in the pharmaceutical composition is less than 75 ppm within the shelf life of the pharmaceutical composition.

[0040] Specifically, the pharmaceutical excipients and their dosage are scientifically formulated according to the type of preparation and performance requirements. For example, fillers can be starch and its derivatives, microcrystalline cellulose, lactose, etc., disintegrants can be low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, etc., glidants can be silicon dioxide, etc., and lubricants can be magnesium stearate, talc, etc., to ensure that the preparation has good process formability, disintegration and solubility.

[0041] The preparation method of the bumetanide composition of the present invention is as follows: (1) Premixing The bumetanide API, the selected antioxidant, and other pharmaceutical excipients (excluding lubricants) are mixed in equal and increasing amounts according to the prescribed ratio in a mixer. The mixing speed is set to 8-25 rpm and the mixing time is 5-30 minutes to ensure thorough mixing. The prescribed amount of lubricant is then added and mixing is continued for 3-10 minutes.

[0042] (2) Granulation Depending on actual production needs, dry granulation or wet granulation process can be selected. In dry granulation, the mixture obtained in step (1) is added to the hopper of a dry granulator, and the roller pressure is set to 1-10 MPa. Dry granules are obtained after roller pressing, crushing, and granulation. Alternatively, wet granulation is adopted, and a binder solution or water is sprayed onto the mixture in step (1), granulated by a high-speed mixing granulator, and the wet granules are dried at 40°C-60°C to obtain dry granules.

[0043] (3) Total mixing The dry granules obtained in step (2) are transferred to a mixing barrel, and an external lubricant is added and mixed evenly.

[0044] (4) Tablet compression or capsule filling The materials directly mixed in step (1) or the materials obtained after granulation and total mixing in step (3) are compressed into tablets using a rotary tablet press, or capsules are filled with a capsule filler to finally obtain a bumetanide preparation that meets the quality standard requirements. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The above and / or additional aspects and advantages of the present application will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which: Figure 1 The results of Maillard impurity detection in the examples and comparative examples of this application are as follows; Figure 2 The test results of the total impurities of the examples and comparative examples of this application are as follows; Figure 3 The test results of nitrosamine impurities in the examples and comparative examples of the present application are as follows; Figure 4 This is the HPLC spectrum of the sample of Comparative Example 1 of this application under accelerated test conditions (40℃±2℃, RH75%±5%) for 6 months. DETAILED DESCRIPTION

[0046] The present invention is further described below by way of examples. For those skilled in the art, based on the teachings of the present invention, equivalent replacement improvements made to the following examples using existing technologies still fall within the scope of protection of the present invention.

[0047] N-nitrosobumetanide detection method Methods The content of chlorinated paracetamol was determined according to the mass spectrometry method (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0431).

[0048] Solvent methanol-water (6:4) Test solution: Take the contents of 5 bumetanide tablets or 5 bumetanide capsules, place them in a 10 ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve the bumetanide, add solvent and dilute to the scale, shake well, filter, and take the filtrate.

[0049] Reference Solution: Take an appropriate amount of N-nitrosobumetanide reference substance, accurately weigh it, dissolve it in solvent and quantitatively dilute it to make a solution containing 37.5 ng per 1 ml.

[0050] Chromatographic conditions: Use octadecylsilane bonded silica gel as the filler (e.g., Agilent ZORBAX EclipsePlus C18, 2.1×50 mm, 1.8 μm or equivalent performance column); 0.1% formic acid in water as mobile phase A, methanol as mobile phase B, gradient elution according to Table 1; flow rate, 0.2 ml / min; column temperature, 30°C; injection volume, 10 μl.

[0051] Table 1

[0052] Mass spectrometry conditions (reference instrument model: Agilent 6470 QQQ liquid spectrometer, parameters can be adjusted according to the specific instrument to meet the detection requirements, and chromatographic conditions parameters can be adjusted synchronously if necessary): ESI+, MRM mode, ion 394.1, Dwell200, Fragmentor 135 (V), Cell Accelerator 5 (V), carrier gas temperature 300°C, carrier gas flow rate 6.0 L / min, nebulizer pressure 45.0 psi, sheath gas temperature 250°C, sheath gas flow rate 11.0 L / min, capillary voltage 3500 V, nozzle voltage 500 V.

[0053] Switching valve control (see Table 2): Table 2

[0054] Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, record the mass spectrum, and calculate the peak area according to the external standard method.

[0055] N-nitrosoBumetanide calculation formula:

[0056] Detection methods for bumetanide-related substances Methods: The content of 1,2-dimethoate was determined according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0057] Solvent acetonitrile-water (4:6) Test solution: Take 10 tablets or 10 granules of this product, place them in a 20ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve bumetanide, add solvent to dilute to the scale, shake well, filter, and take the filtrate.

[0058] Accurately measure 1 ml of the test solution into a 100 ml volumetric flask, dilute to the mark with solvent, and shake well.

[0059] The system suitability solution was bumetanide mixed control solution (a mixed solution containing bumetanide, impurity 87A-1, and impurity 87A-2).

[0060] Chromatographic conditions: Use octadecylsilane bonded silica gel as the filler (e.g., YMC-Pack ODS-A, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent performance) and a trapping column (e.g., Ghost-Buster, 4.6 mm × 50 mm), 0.05% phosphoric acid solution as mobile phase A, acetonitrile as mobile phase B, gradient elution according to Table 3, a flow rate of 1.0 ml per minute; column temperature of 30°C; detection wavelength of 254 nm; injection volume of 10 μl.

[0061] Table 3

[0062] System suitability requirements: In the system suitability solution chromatogram, the separation of adjacent known impurity peaks should meet the requirements.

[0063] Determination method: Accurately measure the test solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0064] Maillard impurity detection method: the same as the above-mentioned bumetanide-related substance detection method.

[0065] Identification of Maillard impurity peaks: In the HPLC chromatogram of the relevant substance, the impurity peak with a retention time (tR) of approximately 14 minutes is the Maillard impurity peak. Its content is quantified by area normalization.

[0066] Maillard impurity calculation formula:

[0067] Example 1 The prescription of bumetanide tablets is shown in Table 4 Table 4 Name of raw materials mg / tablet Bumetanide 1 Soluble starch 100 lactose 50 Ascorbyl palmitate 0.9 Low-substituted hydroxypropyl cellulose 9 colloidal silica 1 magnesium stearate 0.5

[0068] Preparation process: Bumetanide and soluble starch are gradually mixed in equal and increasing amounts, and then ascorbyl palmitate, lactose, low-substituted hydroxypropyl cellulose and colloidal silicon dioxide are added and mixed evenly, and finally magnesium stearate is added and mixed to obtain a bumetanide mixture.

[0069] The bumetanide mixture was directly compressed into tablets using a rotary tablet press by adjusting parameters such as tableting pressure and filling amount to control the hardness to 10~60N.

[0070] Example 2 The prescription of Bumetanide tablets is shown in Table 5 Table 5 Name of raw materials mg / tablet Bumetanide 1 Pregelatinized starch 100 lactose 50 Ascorbyl palmitate 3.5 Low-substituted hydroxypropyl cellulose 9 colloidal silica 2 talcum powder 1 magnesium stearate 0.5 Preparation process: The prescribed amount of bumetanide and pregelatinized starch are gradually mixed in equal and increasing amounts. Ascorbyl palmitate, lactose, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide are added and mixed evenly. Talc is then added and mixed evenly. The bumetanide mixture is thus obtained.

[0071] The bumetanide mixture was dry granulated, the roller pressure was set to 1.5-3 MPa, the upper sieve aperture was 5.0 mm, and the lower sieve aperture was 1.0 mm to obtain dry granules, and then magnesium stearate was added to the total mixture to obtain intermediate product granules.

[0072] The intermediate product granules are pressed into tablets using a rotary tablet press, adjusting parameters such as tableting pressure and filling amount to control the hardness to 10~60N.

[0073] Example 3 The prescription of Bumetanide Capsules is shown in Table 6 Table 6 Name of raw materials mg / tablet Bumetanide 1 microcrystalline cellulose 150 Ascorbyl palmitate 3.5 Croscarmellose sodium 9 Povidone 1 colloidal silica 1 talcum powder 1 magnesium stearate 0.5 Preparation process: The prescribed amount of bumetanide and microcrystalline cellulose are gradually mixed in equal and increasing amounts. Ascorbyl palmitate, croscarmellose sodium, povidone, and colloidal silicon dioxide are added and mixed evenly. Talc is then added and mixed evenly. The bumetanide mixture is thus obtained.

[0074] The bumetanide mixture is sprayed with purified water for wet granulation at a stirring speed of 150-300 rpm and a cutting speed of 1000-2000 rpm. After preparing a soft material, the mixture is passed through a 16-30 mesh screen to obtain wet granules. The wet granules are then dried using a fluidized bed boiling process to obtain dry granules. Magnesium stearate is then added and mixed to obtain intermediate granules. The intermediate granules are then filled into capsules using a capsule filler.

[0075] Example 4 The prescription of Bumetanide Capsules is shown in Table 7 Table 7 Name of raw materials mg / tablet Bumetanide 1 lactose 150 Ascorbyl palmitate 5 Cross-linked polyvinylpyrrolidone 9 colloidal silica 1 talcum powder 1 magnesium stearate 0.5 Preparation process: The prescribed amount of bumetanide and lactose are gradually mixed in equal and increasing amounts, ascorbyl palmitate, crospovidone, and colloidal silicon dioxide are added and mixed evenly, and talc is added and mixed evenly. The bumetanide mixture is thus obtained.

[0076] The bumetanide mixture was dry granulated, the roller pressure was set to 1.5-3 MPa, the upper sieve aperture was 5.0 mm, and the lower sieve aperture was 1.0 mm to obtain dry granules, and then magnesium stearate was added to the total mixture to obtain intermediate product granules.

[0077] The intermediate product granules are pressed into tablets using a rotary tablet press, adjusting parameters such as tableting pressure and filling amount to control the hardness to 10~60N.

[0078] Example 5 The prescription of Bumetanide tablets is shown in Table 8 Table 8 Name of raw materials mg / tablet Bumetanide 1 Soluble starch 100 lactose 50 Propyl gallate 5 Low-substituted hydroxypropyl cellulose 9 colloidal silica 2 talcum powder 1 magnesium stearate 0.5 Preparation process: The prescribed amount of bumetanide and soluble starch are gradually mixed in equal and increasing amounts. Lactose, propyl gallate, low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide are added and mixed evenly. Talc is then added and mixed evenly. The bumetanide mixture is thus obtained.

[0079] The bumetanide mixture was dry granulated, the roller pressure was set to 1.5-3 MPa, the upper sieve aperture was 5.0 mm, and the lower sieve aperture was 1.0 mm to obtain dry granules, and then magnesium stearate was added to the total mixture to obtain intermediate product granules.

[0080] The intermediate product granules are pressed into tablets using a rotary tablet press, adjusting parameters such as tableting pressure and filling amount to control the hardness to 10~60N.

[0081] The prescriptions of comparative examples 1-4 of bumetanide tablets are shown in Table 9: Table 9

[0082] Preparation method: The bumetanide and soluble starch in the prescribed amounts of each comparative example were gradually mixed in equal and increasing amounts, and the prescribed amounts of lactose, antioxidant (caffeic acid, ferulic acid, or ascorbic acid), low-substituted hydroxypropyl cellulose, and colloidal silicon dioxide were added and mixed evenly. Talc was added and mixed evenly to obtain a bumetanide mixture.

[0083] The bumetanide mixture was dry granulated, the roller pressure was set to 1.5-3 MPa, the upper sieve aperture was 5.0 mm, and the lower sieve aperture was 1.0 mm to obtain dry granules, and then magnesium stearate was added to the total mixture to obtain intermediate product granules.

[0084] The intermediate product granules are pressed into tablets using a rotary tablet press, adjusting parameters such as tableting pressure and filling amount to control the hardness to 10~60N.

[0085] Comparative Example 5 The drug was prepared by wet granulation process according to the formulation of the reference preparation Bumetanide tablets (Burinex).

[0086] Table 10

[0087] The prescribed amount of bumetanide is gradually mixed with lactose and corn starch in equal and increasing amounts, povidone, agar and silicon dioxide are added and mixed evenly, and then talc is added and mixed evenly to obtain a bumetanide mixture.

[0088] Add water to polysorbate 80 to prepare a 1% polysorbate 80 aqueous solution. The bumetanide mixture was sprayed with a polysorbate 80 aqueous solution for wet granulation at a stirring paddle speed of 150-300 rpm and a cutter speed of 1000-2000 rpm. After preparing a soft material, the wet granules were passed through a 16-30 mesh sieve. The wet granules were dried using a fluidized bed boiling method to obtain dry granules, and then magnesium stearate was added and mixed to obtain intermediate product granules.

[0089] The intermediate product granules are pressed into tablets using a rotary tablet press, adjusting parameters such as tableting pressure and filling amount to control the hardness to 10~60N.

[0090] Experimental example The above-described examples, comparative examples, and original bumetanide tablet samples were placed under accelerated conditions (40°C ± 2°C, RH 75% ± 5%) for 6 months. Samples were taken at different time points and tested for appearance, related substances, and N-nitrosamine bumetanide impurities.

[0091] Related substance detection methods: Methods: The content of 1,2-dimethoate was determined according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0092] Solvent acetonitrile-water (4:6) Test solution: Take 10 tablets or 10 granules of this product, place them in a 20ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve bumetanide, add solvent to dilute to the scale, shake well, filter, and take the filtrate.

[0093] Accurately measure 1 ml of the test solution into a 100 ml volumetric flask, dilute to the mark with solvent, and shake well.

[0094] The system suitability solution was bumetanide mixed control solution (a mixed solution containing bumetanide, impurity 87A-1, and impurity 87A-2).

[0095] Chromatographic conditions: Use octadecylsilane bonded silica gel as the filler (e.g., YMC-Pack ODS-A, 4.6 mm × 150 mm, 5 μm or a chromatographic column with equivalent performance) and a trapping column (e.g., Ghost-Buster, 4.6 mm × 50 mm), 0.05% phosphoric acid solution as mobile phase A, acetonitrile as mobile phase B, gradient elution according to Table 11, a flow rate of 1.0 ml per minute; column temperature of 30°C; detection wavelength of 254 nm; injection volume of 10 μl.

[0096] Table 11

[0097] System suitability requirements: In the system suitability solution chromatogram, the separation of adjacent known impurity peaks should meet the requirements.

[0098] Determination method: Accurately measure the test solution and control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0099] N-nitrosamine bumetanide impurity detection method: Methods The content of chlorinated paracetamol was determined according to the mass spectrometry method (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0431).

[0100] Solvent methanol-water (6:4) For the test solution, take 5 bumetanide tablets or 5 bumetanide capsules, place them in a 10 ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve the bumetanide, add solvent and dilute to the scale, shake well, filter, and take the filtrate.

[0101] Reference Solution: Take an appropriate amount of N-nitrosobumetanide reference substance, accurately weigh it, dissolve it in solvent and quantitatively dilute it to make a solution containing 37.5 ng per 1 ml.

[0102] Chromatographic conditions: Use octadecylsilane bonded silica gel as the filler (e.g., Agilent ZORBAX EclipsePlus C18, 2.1×50 mm, 1.8 μm or a column of equivalent performance); use 0.1% formic acid in water as mobile phase A and methanol as mobile phase B, with gradient elution according to Table 12; flow rate: 0.2 ml / min; column temperature: 30°C; injection volume: 10 μl.

[0103] Table 12

[0104] Mass spectrometry conditions (reference instrument model: Agilent 6470 QQQ liquid spectrometer, parameters can be adjusted according to the specific instrument to meet the detection requirements, and chromatographic conditions parameters can be adjusted synchronously if necessary): ESI+, MRM mode, ion 394.1, Dwell200, Fragmentor 135 (V), Cell Accelerator 5 (V), carrier gas temperature 300°C, carrier gas flow rate 6.0 L / min, nebulizer pressure 45.0 psi, sheath gas temperature 250°C, sheath gas flow rate 11.0 L / min, capillary voltage 3500 V, nozzle voltage 500 V.

[0105] Switching valve control: Table 13

[0106] Determination Method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph, record the mass spectrum, and calculate the peak area according to the external standard method.

[0107] Under accelerated test conditions (40℃±2℃, RH75%±5%), the appearance properties and related substance test results are shown in Table 14: Table 14

[0108] Under accelerated test conditions (40°C ± 2°C, RH 75% ± 5%), the results of N-nitrosamine bumetanide impurity detection are shown in Table 15: Table 15

[0109] As can be seen from Table 14, under accelerated test conditions (40℃±2℃, RH75%±5%) for 6 months: (1) The inventors discovered through research that the reference formulation of bumetanide tablets (Burinex) contains a large amount of Maillard impurities. The formation of these impurities not only changes the appearance of the drug but may also affect the efficacy and safety of the drug. The Maillard impurity and total impurity content in the reference formulation showed a significant upward trend over time, indicating that the formulation system of the reference formulation has a weak ability to inhibit the Maillard reaction.

[0110] (2) No Maillard impurities were detected in Examples 1-4 of the present invention, and a trace amount was detected in Example 5, which was far lower than that of the reference preparation. This shows that the antioxidants in the example formulas can effectively inhibit the formation of Maillard impurities and related substances.

[0111] (3) The contents of Maillard impurities and related substances in the comparative examples showed a continuous upward trend and were generally higher than those in the examples. This indicates that the antioxidants used in the comparative examples have a weaker control effect on the formation of related substances.

[0112] (4) The appearance of the samples of the examples of the present invention always appears as off-white flakes or contents, while the appearance of the comparative examples 1-3 changes to yellow, which directly affects the product quality and also highlights the advantage of the formula of the present invention in appearance stability.

[0113] (5) In summary, the bumetanide oral solid preparation and its preparation method of the present invention can effectively inhibit the formation of Maillard impurities and related substances while maintaining a good appearance of the preparation, thereby solving the problems existing in the compatibility and stability of bumetanide preparations with conventional raw and auxiliary materials.

[0114] As can be seen from Table 15, under accelerated test conditions (40℃±2℃, RH75%±5%) for 6 months: (1) The nitrosamine impurity content of the preparations prepared in the examples of the present invention is significantly lower than that of the comparative example thiol and bumetanide tablet reference preparations (Burinex), thereby inhibiting the generation of nitrosamine impurities from the initial source.

[0115] (2) In the preparations of Examples 2 and 4 of the present invention, no nitrosamine impurities were detected at 0 months. As the storage time increased, the impurities showed a slow growth trend. However, the initial nitrosamine impurity content in the comparative example and reference preparations was higher than that in the examples, and the growth rate was significantly greater as the storage time increased. This shows that the present invention has a good inhibitory effect on the formation and accumulation of nitrosamine impurities.

[0116] (3) In summary, the bumetanide oral solid preparation and its preparation method of the present invention can effectively inhibit the generation and accumulation of nitrosamine impurities, solve the pain points of safety and stability of bumetanide preparations, and provide a more reliable preparation option for clinical use.

[0117] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present application. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0118] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present application.

Claims

1. A pharmaceutical composition, characterized in that The composition comprises a therapeutically effective amount of bumetanide, one or more antioxidants, and one or more pharmaceutically acceptable excipients, wherein the antioxidant is selected from one or more of a fat-soluble vitamin C derivative or a phenolic antioxidant.

2. The pharmaceutical composition according to claim 1, wherein The fat-soluble vitamin C derivative is ascorbyl palmitate.

3. The pharmaceutical composition according to claim 1, wherein The phenolic antioxidant is propyl gallate.

4. The pharmaceutical composition according to claim 1, wherein The pharmaceutical excipients include one or more of a filler, a disintegrant, a binder, a glidant and a lubricant.

5. The pharmaceutical composition according to claim 4, wherein The filler is selected from one or more of starch and its derivatives, lactose, microcrystalline cellulose, and mannitol.

6. The pharmaceutical composition according to claim 4, wherein The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose.

7. The pharmaceutical composition according to claim 4, wherein The binder is selected from one or more of povidone, hypromellose, and hydroxypropyl cellulose.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that After exposure of the pharmaceutical composition to 40°C / 75% RH for a period of 2 months, the amount of the N-nitrosamine bumetanide impurity was less than 75 ppm.

9. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that After exposing the pharmaceutical composition to 40°C / 75% RH for a period of 6 months, the amount of the N-nitrosamine bumetanide impurity was less than 75 ppm.

10. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that The pharmaceutical composition has an N-nitrosamine bumetanide impurity content of less than 75 ppm within the drug's shelf life.

11. A method for improving the stability of a bumetanide pharmaceutical composition, characterized in that: The method comprises mixing bumetanide with one or more antioxidants selected from one or more of a fat-soluble vitamin C derivative or a phenolic antioxidant.

12. The method according to claim 11, characterized in that The fat-soluble vitamin C derivative is ascorbyl palmitate; and the phenolic antioxidant is propyl gallate.

13. The method according to claim 11, characterized in that The method further comprises adding pharmaceutical excipients; the pharmaceutical excipients include one or more of fillers, disintegrants, binders, glidants and lubricants.

14. A pharmaceutical composition prepared according to the method according to any one of claims 11 to 13, characterized in that: The pharmaceutical composition has an N-nitrosamine bumetanide impurity amount of less than 75 ppm after exposure to 40° C. / 75% RH for a period of 2 months.

15. A pharmaceutical composition prepared according to the method according to any one of claims 11 to 13, characterized in that: The pharmaceutical composition has an N-nitrosamine bumetanide impurity amount of less than 75 ppm after exposure to 40° C. / 75% RH for a period of 6 months.

16. A pharmaceutical composition prepared according to the method according to any one of claims 11 to 13, characterized in that: The pharmaceutical composition has an N-nitrosamine bumetanide impurity content of less than 75 ppm within the drug's shelf life.

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