An oral solid preparation of bumetanide with improved stability and a method for preparing the same

Abstract

The present application provides a kind of pharmaceutical composition, the composition comprises therapeutically effective amount of bucumidol, one or more specific antioxidants and other necessary one or more pharmaceutically acceptable pharmaceutical adjuvant, the specific antioxidant is selected from one or more of the following: lipid-soluble vitamin C derivative, or phenolic antioxidant.In addition, a method for improving the stability of bucumidol pharmaceutical composition is also disclosed.The technical scheme of the present application effectively solves the problem of the generation and growth of N-nitroso-bumetanide and other related substances in the production and storage of bucumidol solid preparation, significantly improves the stability of the drug and the safety of drug use.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a pharmaceutical composition and method for effectively solving the generation and growth of N-nitroso-bumetanide and other related substances of bumetanide drug combination during production and storage. BACKGROUND

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

[0003]

[0004] As an important derivative of m-aminobenzenesulfonamide, bumetanide can reach a peak drug concentration in the plasma within 1 to 2 hours after oral administration. The drug is mainly metabolized in the liver, and its mechanism of action is to inhibit the active transport of chloride ions and the passive reabsorption of sodium ions by the loop of Henle, thereby exerting significant diuretic effect. It is a highly effective diuretic drug widely used in clinical practice.

[0005] Due to the presence of a secondary amine group in the molecular structure of bumetanide, the secondary amine group is prone to chemical reaction with nitrite contained in pharmaceutical excipients during the production process of drug preparation and during storage, thereby generating N-nitrosamine bumetanide impurities. This impurity is a potential carcinogen, which significantly increases the potential safety risk of patients during medication. The generation mechanism of N-nitrosamine bumetanide impurities is shown in formula (B):

[0006]

[0007] The nitrosamine structure is characterized by the direct bonding of a nitroso group and an amine group. During in vivo metabolism, it can be converted into an alkyl diazonium ion. This ion can specifically act on the nitrogen and oxygen atoms contained in the base components of DNA molecules such as guanine, cytosine, and thymine, thereby triggering DNA alkylation modification, causing DNA base pairs to mismatch, and causing gene mutations, thereby posing a potential carcinogenic risk to living organisms.

[0008] From the perspective of impurity control, nitrosamine impurities have high chemical stability, and conventional treatment methods are difficult to effectively remove them. Moreover, as the storage period of the drug is prolonged, the content of the drug may show a continuous growth trend.

[0009] In view of the clear 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. According to the relevant guidelines issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), based on the toxicology concern threshold method, the acceptable daily intake of nitrosamine impurities is 1.5 μg / day. This standard fully considers the tolerance differences of different populations, as well as factors such as drug use period and administration route, and aims to control the carcinogenic risk of patients taking drugs for a lifetime to less than one in 100,000. In drug quality control, the limit of impurities in the drug is calculated according to the maximum daily intake of the drug. The maximum daily intake of the drug is 20 mg, so the limit of nitrosamine impurities in the drug is calculated as follows: 1.5 μg / day ÷ 20 mg × 10 6 Therefore, the control limit of nitrosamine impurities in bumetanide drugs is 75 ppm.

[0010] Currently, there are many difficulties in attempts to inhibit the generation of nitrosamine impurities. For example, some literature reports that by adding alkaline excipients to adjust the pH value of the formula, adding antioxidants (caffeic acid, ferulic acid, ascorbic acid), etc. to reduce the risk of nitrosamine impurities. However, the above methods can cause the generation of unknown impurities in the formula, and the introduction of other unknown impurities due to the degradation of these excipients themselves, and cannot well control the growth of impurities under accelerated and long-term test conditions. The compatibility of bumetanide is not good.

[0011] Patent CN 118680914 A discloses a bumetanide composition and a preparation method thereof, which adds stabilizers magnesium oxide and meglumine to the formula, and uses airflow crushing, wet granulation, and boiling granulation, etc. The technical solution has certain limitations. On the one hand, the complex formula system and multi-step preparation process increase the technical difficulty and cost of industrial production, and it is difficult to meet the efficiency demand of large-scale industrial production; on the other hand, the composition and process have no obvious effect on the control of related substances and specific impurities (such as Maillard impurities), and cannot effectively guarantee the quality stability of the drug.

[0012] In view of the deficiencies of the prior art in the control of N-nitrosobumetanide impurities and bumetanide related substances, there is an urgent need to develop an efficient and feasible method that can effectively inhibit the generation of the above impurities, thereby improving the quality of bumetanide preparations and ensuring the safety of clinical drug use. SUMMARY

[0013] The present inventors have developed a bumetanide solid preparation that can effectively inhibit the generation of N-nitrosamine bumetanide impurities and other related substances during the production and storage of the preparation.

[0014] Specifically, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of bumetanide, one or more antioxidants selected from one or more of a lipid-soluble vitamin C derivative, or a phenolic antioxidant, and one or more pharmaceutically acceptable pharmaceutical excipients. The lipid-soluble vitamin C derivative, by virtue of its unique lipid-solubility property, can be uniformly dispersed in the material system, effectively capturing free radicals and blocking the impurity generation path initiated by the oxidation reaction; the phenolic antioxidant, by providing hydrogen atoms, quenches free radicals and inhibits the oxidation chain reaction. The rational selection of these antioxidants provides a strong guarantee for impurity inhibition from the molecular mechanism level.

[0015] In a preferred embodiment of the present application, the lipid-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.

[0016] In a preferred embodiment of the present application, 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.

[0017] In a preferred embodiment of the present application, the pharmaceutical excipients include one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0018] In a preferred embodiment of the present application, the filler is selected from one or more of starch and its derivatives, lactose, microcrystalline cellulose, mannitol; preferably, the filler includes lactose or starch; more preferably, the mass of the filler accounts for 70-95% of the total mass of the pharmaceutical composition.

[0019] In a preferred embodiment of the present application, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose. More preferably, the mass of the disintegrant accounts for 1-10% of the total mass of the pharmaceutical composition.

[0020] In a preferred embodiment of the present application, the binder is selected from one or more of povidone, hypromellose, hydroxypropyl cellulose. More preferably, the mass of the binder accounts for 0.1-5% of the total mass of the pharmaceutical composition.

[0021] In a preferred embodiment of the present application, 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.

[0022] In a preferred embodiment of the present application, the lubricant is selected from one or more of magnesium stearate, talc, magnesium stearate fumarate. More preferably, the lubricant is present in an amount of 0.05-3% by weight of the total weight of the pharmaceutical composition.

[0023] In a preferred embodiment of the present application, the amount of N-nitrosamine bumetanide impurity is less than 75 ppm after the pharmaceutical composition is exposed to 40°C / 75% RH for a period of 2 months. The amount of N-nitrosamine bumetanide impurity is determined by high performance liquid chromatography (HPLC).

[0024] Preferably, the amount of N-nitrosamine bumetanide impurity is less than 75 ppm after the pharmaceutical composition is exposed to 40°C / 75% RH for a period of 6 months.

[0025] More preferably, the amount of N-nitrosamine bumetanide impurity is less than 75 ppm during the shelf life of the pharmaceutical product. The shelf life of a pharmaceutical product generally refers to the period of time during which the product is in a form that is ready for sale to the consumer, during which the product is suitable for use by a patient. The term "shelf life" also refers to the period of time during which a pharmaceutical product is capable of maintaining its quality, safety and effectiveness under specified storage conditions. During this period, the ingredients, content, properties, etc. of the product meet the requirements of the national pharmaceutical standards or pharmaceutical registration standards, and the product can be used safely and effectively. The shelf life of a pharmaceutical product can be greater than 3 months, 6 months, 12 months, 18 months, 24 months, and preferably 36 months. The specified storage conditions for a pharmaceutical product are, for example, "in a cool, dry, dark place, and the temperature should not exceed 25°C" or "store in a light-protected, airtight container".

[0026] In a preferred embodiment of the present application, the pharmaceutical composition is a solid formulation or a liquid formulation; preferably, the solid formulation is a powder, granules, tablets or capsules.

[0027] In particular, in a preferred embodiment of the present application, the composition comprises a therapeutically effective amount of bumetanide, one or more antioxidants selected from one or more of ascorbyl palmitate, propyl gallate, and one or more pharmaceutically acceptable pharmaceutical excipients. Preferably, the amount of bumetanide is 0.1-2% by weight of the total weight of the pharmaceutical composition.

[0028] In a second aspect, the present application provides a method for improving the stability of a bumetanide pharmaceutical composition, the method comprising mixing bumetanide with one or more antioxidants selected from one or more of a fat-soluble vitamin C derivative, or a phenolic antioxidant.

[0029] In a preferred embodiment of the present application, the fat-soluble vitamin C derivative is ascorbyl palmitate.

[0030] In a preferred embodiment of the present application, the phenolic antioxidant is propyl gallate.

[0031] In a preferred embodiment of the present application, the antioxidant is present in an amount of 0.5% to 3% by weight of the total weight of the pharmaceutical composition.

[0032] In a preferred embodiment of the present application, the method comprises mixing bumetanide with one or more antioxidants and pharmaceutical excipients; the pharmaceutical excipients comprise one or more of a filler, a disintegrant, a binder, a glidant and a lubricant.

[0033] In a preferred embodiment of the present application, the filler is selected from one or more of starch and its derivatives, lactose, microcrystalline cellulose, mannitol; more preferably, the filler comprises lactose or starch.

[0034] In a preferred embodiment of the present application, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyplasdone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose.

[0035] In a preferred embodiment of the present application, the binder is selected from one or more of povidone, hypromellose, hydroxypropyl cellulose.

[0036] In a preferred embodiment of the present application, the pharmaceutical composition prepared by the aforementioned method has an amount of N-nitrosamine bumetanide impurities of less than 75 ppm after being exposed to 40°C / 75% RH for 2 months; the amount of N-nitrosamine bumetanide impurities is determined by high performance liquid chromatography (HPLC). Preferably, the pharmaceutical composition prepared by the aforementioned method has an amount of Maillard impurities of less than 0.5% after being exposed to 40°C / 75% RH for 2 months. The amount of Maillard impurities refers to the content determined by high performance liquid chromatography (HPLC) by area normalization method.

[0037] In a preferred embodiment of the present application, the Maillard impurity refers to an impurity generated by the reaction of bumetanide with pharmaceutical excipients, and the specific structure is shown in formula (C):

[0038]

[0039] In a preferred embodiment of the present application, the pharmaceutical composition prepared by the aforementioned method has an amount of N-nitrosamine bumetanide impurities of less than 75 ppm after being exposed to 40°C / 75% RH for 6 months; preferably, the pharmaceutical composition prepared by the aforementioned method has an amount of Maillard impurities of less than 0.5% after being exposed to 40°C / 75% RH for 6 months.

[0040] In a preferred embodiment of the present application, the pharmaceutical composition prepared by the aforementioned method has an amount of N-nitrosamine bumetanide impurities of less than 75 ppm within the shelf life of the drug product; preferably, the pharmaceutical composition prepared by the aforementioned method has an amount of Maillard impurities of less than 0.5% within the shelf life of the drug product.

[0041] In a third aspect, the present application provides a pharmaceutical composition prepared according to the method of the second aspect, which has an amount of N-nitrosamine bumetanide impurities of less than 75 ppm after being exposed to 40℃ / 75%RH for 2 months. Preferably, the pharmaceutical composition has an amount of Maillard impurities of less than 0.5% after being exposed to 40℃ / 75%RH for 2 months.

[0042] In a preferred embodiment of the present application, the present application provides a pharmaceutical composition prepared according to the method of the second aspect, which has an amount of N-nitrosamine bumetanide impurities of less than 75 ppm after being exposed to 40℃ / 75%RH for 6 months. Preferably, the pharmaceutical composition has an amount of Maillard impurities of less than 0.5% after being exposed to 40℃ / 75%RH for 6 months.

[0043] In a preferred embodiment of the present application, the present application provides a pharmaceutical composition prepared according to the method of the second aspect, which has an amount of N-nitrosamine bumetanide impurities of less than 75 ppm within the shelf life of the drug product. The pharmaceutical composition has an amount of N-nitrosamine bumetanide impurities of less than 75 ppm within the shelf life of the drug product.

[0044] Specifically, the pharmaceutical excipients and their amounts are scientifically matched according to the type and performance requirements of the preparation, such as starch and its derivatives, microcrystalline cellulose, lactose, etc. for fillers, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, etc. for disintegrants, silicon dioxide, etc. for glidants, magnesium stearate, talc, etc. for lubricants, to ensure that the preparation has good process formability, disintegrability and dissolution rate.

[0045] The preparation method of the bumetanide composition of the present application is specifically as follows:

[0046] (1) Pre-mixing

[0047] The bumetanide drug substance and the selected antioxidant and other pharmaceutical excipients except lubricants are mixed in the mixing machine in an equal incremental manner according to the prescription ratio, the mixing speed is set to 8-25 revolutions per minute, and the mixing time is 5-30 minutes, so that the materials are fully mixed, and then the prescription amount of lubricant is added and mixed for another 3-10 minutes.

[0048] (2) Granulation

[0049]

[0049] According to the actual production needs, dry granulation or wet granulation process can be selected. When dry granulation is selected, the mixture obtained in step (1) is added into the hopper of a dry granulator, the roller pressure is set to 1-10 MPa, and after roller compression, crushing and granulation, dry granules are obtained; or wet granulation is adopted, the adhesive solution or water is sprayed into the mixture of step (1), and the mixture is granulated by a high-speed mixing granulator, and after drying at 40-60°C, dry granules are obtained.

[0050] (3) Total mixing

[0051] The dry granules obtained in step (2) are transferred to a mixing barrel, and an additional lubricant is added and uniformly mixed.

[0052] (4) Tabletting or capsule filling

[0053] The direct mixture of step (1) or the material obtained after total mixing granulation of step (3) is tabletted by a rotary tablet press or filled into capsules using a capsule filler, and finally a bumetanide preparation meeting the quality standard requirements is obtained. BRIEF DESCRIPTION OF DRAWINGS

[0054] The above and / or additional aspects and advantages of the present application will become apparent and be readily understood from the following description, including the accompanying drawings, in which:

[0055] Figure 1 The detection results of Maillard impurities of the examples and comparative examples of the present application are shown in Table 1.

[0056] Figure 2 The detection results of total impurities of the examples and comparative examples of the present application are shown in Table 2.

[0057] Figure 3 The detection results of nitrosamine impurities of the examples and comparative examples of the present application are shown in Table 3.

[0058] Figure 4 The HPLC spectrum of the sample of Comparative Example 1 under the accelerated (40°C±2°C, RH 75%±5%) test conditions for 6 months is shown in Figure 1. DETAILED DESCRIPTION

[0059] The present application will be further described by the following examples. For those skilled in the art, according to the teachings of the present application, equivalent alternative improvements to the following examples using prior art still fall within the scope of the present application.

[0060] N-nitroso-bumetanide detection method

[0061] The method is determined by mass spectrometry (Chinese Pharmacopoeia 2020 Edition Part IV General 0431).

[0062] Solvent methanol-water (6:4)

[0063] Take the contents of 5 tablets of bumetanide or 5 capsules of bumetanide, 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 mark, shake well, filter, and take the filtrate.

[0064] Take the N-nitroso-bumetanide reference substance, accurately weigh, dissolve in solvent, and dilute to make a solution containing 37.5 ng per 1 ml.

[0065] Chromatographic conditions: octadecylsilane-bonded silica gel as the filler (such as: Agilent ZORBAX Eclipse Plus C18, 2.1 x 50 mm, 1.8 μm or a chromatographic column with equivalent performance); 0.1% formic acid in water as mobile phase A, methanol as mobile phase B, gradient elution according to Table 1; flow rate of 0.2 ml per minute; column temperature of 30°C; injection volume of 10 μl.

[0066] Table 1

[0067]

[0068] Mass spectrometry conditions (reference instrument model: Agilent 6470 QQQ liquid chromatograph-mass spectrometer, parameters can be adjusted according to the specific instrument to meet the detection requirements, if necessary, adjust the chromatographic condition parameters synchronously): ESI+, MRM mode, ion 394.1, Dwell 200, Fragmentor 135 (V), Cell Accelerator 5 (V), carrier gas temperature 300°C, carrier gas flow rate 6.0 L per minute, atomizer pressure 45.0 psi, sheath gas temperature 250°C, sheath gas flow rate 11.0 L per minute, capillary voltage 3500 V, nozzle voltage 500 V.

[0069] Switching valve control (see Table 2):

[0070] Table 2

[0071]

[0072] Determination: accurately pipette the test sample solution and the reference substance solution into the liquid chromatograph, record the mass spectrum, and calculate the peak area by the external standard method.

[0073] N-nitroso-bumetanide calculation formula:

[0074]

[0075] Detection method of bumetanide related substances

[0076] Method: determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four general rules 0512).

[0077] Solvent Acetonitrile-water (4:6)

[0078] Take 10 tablets or 10 pellets of the product, place them in a 20 ml volumetric flask, add an appropriate amount of solvent, and sonicate to dissolve the bumetanide. Dilute to the mark with solvent, shake well, and filter. Take the filtrate.

[0079] Take 1 ml of the test solution, place it in a 100 ml volumetric flask, and dilute to the mark with solvent. Shake well.

[0080] System suitability solution Take the bumetanide mixed control solution (a mixed solution containing bumetanide, impurity 87A-1, and impurity 87A-2).

[0081] Chromatographic conditions Use octadecylsilane-bonded silica gel as the filler (such as YMC-Pack ODS-A, 4.6 mm x 150 mm, 5 μm or a chromatographic column with equivalent performance) and a trap column (such as Ghost-Buster, 4.6 mm x 50 mm), use 0.05% phosphoric acid solution as mobile phase A and acetonitrile as mobile phase B, perform gradient elution according to Table 3 at a flow rate of 1.0 ml per minute, the column temperature is 30°C, the detection wavelength is 254 nm, and the injection volume is 10 μl.

[0082] Table 3

[0083]

[0084] System suitability The resolution of adjacent known impurity peaks in the chromatogram of the system suitability solution should meet the requirements.

[0085] Determination method Take the test solution and the control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0086] Maillard impurity detection method: same as the above-mentioned bumetanide related substance detection method.

[0087] Maillard impurity peak determination: in the related substance HPLC chromatogram, the impurity peak with a retention time (tR) of about 14 min is the Maillard impurity peak. Its content is detected and quantified by the area normalization method.

[0088] Maillard impurity calculation formula:

[0089]

[0090] Example 1

[0091] The bumetanide tablet prescription is shown in Table 4

[0092] Table 4

[0093] Ingredient name mg / tablet Bumetanide 1 Soluble starch 100 Lactose 50 Ascorbyl palmitate 0.9 Low-substituted hydroxypropyl cellulose 9 Colloidal silicon dioxide 1 Magnesium stearate 0.5

[0094] Preparation process:

[0095] The bumetanide and soluble starch were mixed gradually by equal incremental mixing method, then ascorbic acid palmitate, lactose, low-substituted hydroxypropyl cellulose and colloidal silicon dioxide were mixed uniformly, and finally magnesium stearate was added and mixed uniformly, to obtain a bumetanide mixture.

[0096] The bumetanide mixture was directly compressed into tablets by a rotary tablet press, with the tablet hardness controlled at 10-60 N by adjusting the tabletting pressure, filling amount and other parameters.

[0097] Example 2

[0098] The prescription of the bumetanide tablet is shown in Table 5

[0099] Table 5

[0100] Ingredient name mg / tablet Bumetanide 1 Pre-gelatinized starch 100 Lactose 50 Ascorbyl palmitate 3.5 Low-substituted hydroxypropyl cellulose 9 Colloidal silicon dioxide 2 Talc 1 Magnesium stearate 0.5

[0101] Preparation process:

[0102] The prescription amount of bumetanide and pregelatinized starch were mixed gradually by equal incremental mixing method, ascorbic acid palmitate, lactose, low-substituted hydroxypropyl cellulose and colloidal silicon dioxide were mixed uniformly, and talc was added and mixed uniformly, to obtain a bumetanide mixture.

[0103] The bumetanide mixture was dry granulated, with the pressure roller pressure set at 1.5-3 MPa, the upper sieve mesh size for granulation set at 5.0 mm, and the lower sieve mesh size set at 1.0 mm, to obtain dry granules, and then additional magnesium stearate was added to obtain intermediate product granules.

[0104] The intermediate product granules were compressed into tablets by a rotary tablet press, with the tablet hardness controlled at 10-60 N by adjusting the tabletting pressure, filling amount and other parameters.

[0105] Example 3

[0106] The prescription of the bumetanide capsule is shown in Table 6

[0107] Table 6

[0108] Ingredient name mg / tablet Bumetanide 1 Microcrystalline cellulose 150 Ascorbyl palmitate 3.5 Croscarmellose sodium 9 Polyvidone 1 Colloidal silicon dioxide 1 Talc 1 Magnesium stearate 0.5

[0109] Preparation process:

[0110] The prescription amount of bumetanide and microcrystalline cellulose were mixed gradually by equal incremental mixing method, ascorbic acid palmitate, cross-linked sodium carboxymethyl cellulose, povidone and colloidal silicon dioxide were mixed uniformly, and talc was added and mixed uniformly, to obtain a bumetanide mixture.

[0111] The mixture of bumetanide is sprayed into purified water for wet granulation, the stirring paddle speed is 150-300 rpm, the cutter speed is 1000-2000 rpm, the soft material is passed through a 16-30 mesh screen to obtain wet granules, the wet granules are dried by fluidized bed boiling to obtain dry granules, and then the intermediate product granules are obtained after adding additional magnesium stearate. The intermediate product granules are filled into capsules using a capsule filler.

[0112] Example 4

[0113] The prescription of bumetanide capsules is shown in Table 7

[0114] Table 7

[0115] Ingredient name mg / tablet Bumetanide 1 Lactose 150 Ascorbyl palmitate 5 Crospovidone 9 Colloidal silicon dioxide 1 Talc 1 Magnesium stearate 0.5

[0116] Preparation process:

[0117] The prescription amount of bumetanide is mixed with lactose in an equal incremental mixing manner, ascorbic palmitate, cross-linked povidone and colloidal silicon dioxide are added and mixed uniformly, and talc is added and mixed uniformly. The mixture of bumetanide is obtained.

[0118] The mixture of bumetanide is dry granulated, the pressure roller pressure is set to 1.5-3 MPa, the upper screen aperture is 5.0 mm, and the lower screen aperture is 1.0 mm, to obtain dry granules, and then the intermediate product granules are obtained after adding additional magnesium stearate.

[0119] The intermediate product granules are compressed into tablets by adjusting the tabletting pressure, filling amount and other parameters of the rotary tablet press, and the hardness is controlled to be 10-60 N.

[0120] Example 5

[0121] The prescription of bumetanide tablets is shown in Table 8

[0122] Table 8

[0123] Ingredient name mg / tablet Bumetanide 1 Soluble starch 100 Lactose 50 Propyl gallate 5 Low-substituted hydroxypropyl cellulose 9 Colloidal silicon dioxide 2 Talc 1 Magnesium stearate 0.5

[0124] Preparation process:

[0125] The prescription amount of bumetanide is mixed with soluble starch in an equal incremental mixing manner, lactose, propyl gallate, low-substituted hydroxypropyl cellulose and colloidal silicon dioxide are added and mixed uniformly, and talc is added and mixed uniformly. The mixture of bumetanide is obtained.

[0126] The mixture of bumetanide is dry granulated, the pressure roller pressure is set to 1.5-3 MPa, the upper screen aperture is 5.0 mm, and the lower screen aperture is 1.0 mm, to obtain dry granules, and then the intermediate product granules are obtained after adding additional magnesium stearate.

[0127] The intermediate product granules are compressed into tablets by using a rotary tablet press, adjusting the tabletting pressure, filling amount and other parameters, and controlling the hardness to be 10-60 N.

[0128] The prescription of the bumentanide tablets of Comparative Examples 1-4 is shown in Table 9:

[0129] Table 9

[0130]

[0131] Preparation method:

[0132] The prescription amount of bumentanide of each comparative example is mixed with soluble starch in an equal incremental manner, and then the prescription amount of lactose, antioxidant (caffeic acid, ferulic acid or ascorbic acid), low-substituted hydroxypropyl cellulose and colloidal silicon dioxide are added and mixed uniformly, and talc is added and mixed uniformly to obtain a bumentanide mixture.

[0133] The bumentanide mixture is dry granulated, the pressure roller pressure is set to 1.5-3 MPa, the upper screen mesh size is 5.0 mm, and the lower screen mesh size is 1.0 mm, to obtain dry granules, and then the additional magnesium stearate is added and mixed to obtain intermediate product granules.

[0134] The intermediate product granules are compressed into tablets by using a rotary tablet press, adjusting the tabletting pressure, filling amount and other parameters, and controlling the hardness to be 10-60 N.

[0135] Comparative Example 5

[0136] According to the prescription of the reference bumentanide tablet (Burinex), a wet granulation process is used for preparation.

[0137] Table 10

[0138]

[0139] The prescription amount of bumentanide is mixed with lactose and corn starch in an equal incremental manner, and then povidone, agar and silicon dioxide are added and mixed uniformly, and talc is added and mixed uniformly to obtain a bumentanide mixture.

[0140] The polysorbate 80 is dissolved in water to prepare a 1% polysorbate 80 aqueous solution,

[0141] The bumentanide mixture is sprayed into the polysorbate 80 aqueous solution for wet granulation, the stirring paddle speed is 150-300 rpm, the cutter speed is 1000-2000 rpm, the soft material is sieved through a 16-30 mesh screen to obtain wet granules, the wet granules are dried in a fluidized bed to obtain dry granules, and then the additional magnesium stearate is added and mixed to obtain intermediate product granules.

[0142] The intermediate product granules are compressed into tablets by using a rotary tablet press, adjusting the tablet pressing pressure, filling amount and other parameters, and controlling the hardness to be 10-60 N.

[0143] Experimental Example

[0144] The above examples, comparative examples and the original research sample of the bumetanide tablet were placed under accelerated (40℃±2℃, RH 75%±5%) conditions for 6 months, and samples were taken at different time points for detection of appearance, related substances and N-nitrosamine bumetanide impurities.

[0145] Related substance detection method:

[0146] The method is determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rule 0512).

[0147] Solvent acetonitrile-water (4:6)

[0148] The test solution was prepared by taking 10 tablets or 10 granules of the product, placing them in a 20ml volumetric flask, adding an appropriate amount of solvent, ultrasonically dissolving the bumetanide, diluting to the mark with solvent, shaking well, and filtering.

[0149] The control solution was prepared by accurately measuring 1ml of the test solution into a 100ml volumetric flask and diluting to the mark with solvent, shaking well.

[0150] The system suitability solution was prepared by taking a mixture of bumetanide control solution (containing a mixture of bumetanide, impurity 87A-1 and impurity 87A-2).

[0151] The chromatographic conditions were as follows: octadecylsilane-bonded silica gel as the filler (such as YMC-Pack ODS-A, 4.6mm×150mm, 5μm or a chromatographic column with equivalent performance) and a trap column (such as Ghost-Buster, 4.6mm×50mm), 0.05% phosphoric acid solution as mobile phase A, acetonitrile as mobile phase B, gradient elution according to Table 11, flow rate of 1.0ml per minute; column temperature of 30℃; detection wavelength of 254nm; injection volume of 10μl.

[0152] Table 11

[0153]

[0154] The system suitability solution chromatogram should meet the requirements of the separation degree of adjacent known impurity peaks.

[0155] The test solution and the control solution were accurately measured and injected into the liquid chromatograph, and the chromatogram was recorded.

[0156] N-nitrosamine bumetanide impurity detection method:

[0157] Method: Determined by mass spectrometry (ChP 2020 Vol IV 0431).

[0158] Solvent: Methanol-water (6:4)

[0159] Take 5 tablets or 5 capsules of the test sample, place them in a 10 ml volumetric flask, add an appropriate amount of solvent, and ultrasonically dissolve the bumetanide. Add solvent and dilute to the mark, shake well, filter, and take the filtrate.

[0160] Take an appropriate amount of N-nitroso-bumetanide reference substance, accurately weigh, dissolve in solvent, and dilute to make a solution containing 37.5 ng per 1 ml.

[0161] Chromatographic conditions: Use octadecylsilane-bonded silica gel as the filler (such as Agilent ZORBAX Eclipse Plus C18, 2.1 x 50 mm, 1.8 μm or a chromatographic column with equivalent performance); use 0.1% formic acid solution as mobile phase A and methanol as mobile phase B, perform gradient elution according to Table 12; flow rate is 0.2 ml per minute; column temperature is 30°C; injection volume is 10 μl.

[0162] Table 12

[0163]

[0164] Mass spectrometry conditions (reference instrument model: Agilent 6470 QQQ liquid chromatograph-mass spectrometer, parameters can be adjusted according to the specific instrument to meet the detection requirements, if necessary, adjust the chromatographic condition parameters simultaneously): ESI+, MRM mode, ion 394.1, Dwell 200, Fragmentor 135 (V), Cell Accelerator 5 (V), carrier gas temperature 300°C, carrier gas flow rate 6.0 L per minute, atomizer pressure 45.0 psi, sheath gas temperature 250°C, sheath gas flow rate 11.0 L per minute, capillary voltage 3500 V, nozzle voltage 500 V.

[0165] Switching valve control:

[0166] Table 13

[0167]

[0168] Determination: Accurately take the test sample solution and the reference substance solution, inject them into the liquid chromatograph respectively, and record the mass spectrum. Calculate by the external standard method with peak area.

[0169] Under accelerated (40°C ± 2°C, RH 75% ± 5%) test conditions, the appearance and related substance test results are shown in Table 14:

[0170] Table 14

[0171]

[0172] The N-nitrosamine bumentanide impurity detection results under accelerated (40℃±2℃, RH 75%±5%) test conditions are shown in Table 15:

[0173] Table 15

[0174]

[0175] As can be seen from Table 14, under accelerated test conditions (40℃±2℃, RH 75%±5%) for 6 months:

[0176] (1) The inventors found through research that there are more Maillard impurities in the bumentanide tablet reference preparation (Burinex), and the generation of the impurities not only changes the appearance of the drug, but also may affect the effectiveness and safety of the drug. The content of Maillard impurities and total impurities in the reference preparation increases significantly over time, indicating that the formula system of the reference preparation has weak inhibitory ability on the Maillard reaction.

[0177] (2) The Maillard impurities in Examples 1-4 of the present application are not detected, and a small amount is detected in Example 5, which is much lower than the reference preparation. This shows that the antioxidants in the example formula can effectively inhibit the generation of Maillard impurities and related substances.

[0178] (3) The content of Maillard impurities and related substances in the comparative examples shows a continuous upward trend and is generally higher than that of the examples. This shows that the antioxidant selected in the comparative example has weak control effect on the generation of related substances.

[0179] (4) The appearance of the sample of the present application is always white or the content, while the appearance of Comparative Examples 1-3 changes yellow, which directly affects the product quality and highlights the advantages of the formula of the present application in appearance stability.

[0180] (5) In summary, the bumentanide oral solid preparation and the preparation method thereof of the present application can effectively inhibit the generation of Maillard impurities and related substances, while maintaining good appearance of the preparation, and solve the problems existing in the compatibility and stability of conventional raw and auxiliary materials of bumentanide preparations.

[0181] As can be seen from Table 15, under accelerated test conditions (40℃±2℃, RH 75%±5%) for 6 months:

[0182] (1) The content of nitrosamine impurities in the preparation prepared by the present application is significantly lower than that of the thiol and bumentanide tablet reference preparation (Burinex), which inhibits the generation of nitrosamine impurities from the initial source.

[0183] (2) The preparation of Example 2 and Example 4 of the present application did not detect nitrosamine impurities at 0 month, and with the extension of storage time, the impurities showed a slow growth trend. The initial content of nitrosamine impurities in the comparative example and the reference preparation was higher than that of the examples, and with the extension of storage time, the growth rate was significantly greater. It shows that the present application has good inhibition effect on the generation and accumulation of nitrosamine impurities.

[0184] (3) In summary, the bumetanide oral solid preparation and the preparation method thereof of the present application can effectively inhibit the generation and accumulation of nitrosamine impurities, solve the safety and stability pain points of bumetanide preparation, and provide more reliable preparation selection for clinical medication.

[0185] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description of the above terms is not necessarily directed to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. Furthermore, the person skilled in the art can combine and combine the different embodiments or examples described in the present specification and the features of the different embodiments or examples without contradiction.

[0186] 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 limiting the present application, and the person skilled in the art can make changes, modifications, replacements and variations to the above embodiments within the scope of the present application.

Claims

1. A pharmaceutical composition, characterized by, The composition comprises a therapeutically effective amount of bumetanide, an antioxidant selected from ascorbyl palmitate or propyl gallate, and one or more pharmaceutically acceptable pharmaceutical excipients.

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

3. The pharmaceutical composition of claim 2, wherein The filler is selected from one or more of starch and its derivatives, lactose, microcrystalline cellulose, mannitol.

4. The pharmaceutical composition of claim 2, wherein The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyplione, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose.

5. The pharmaceutical composition of claim 2, wherein The binder is selected from one or more of povidone, hypromellose, hydroxypropyl cellulose.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The amount of N-nitrosamine bumetanide impurities is less than 75 ppm after the pharmaceutical composition is exposed to 40°C / 75% RH for a period of 2 months.

7. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The amount of N-nitrosamine bumetanide impurities is less than 75 ppm after the pharmaceutical composition is exposed to 40°C / 75% RH for a period of 6 months.

8. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The amount of N-nitrosamine bumetanide impurities is less than 75 ppm over the shelf life of the pharmaceutical composition.

9. A method of preparing a stable pharmaceutical composition of bumetanide, characterized in that, The method comprises mixing bumetanide with an antioxidant selected from ascorbyl palmitate or propyl gallate.

10. A pharmaceutical composition prepared according to the method of claim 9, wherein, The amount of N-nitrosamine bumetanide impurities is less than 75 ppm after the pharmaceutical composition is exposed to 40°C / 75% RH for a period of 2 months.

11. A pharmaceutical composition prepared according to the method of claim 9, wherein, The amount of N-nitrosamine bumetanide impurities is less than 75 ppm after the pharmaceutical composition is exposed to 40°C / 75% RH for a period of 6 months.

12. A pharmaceutical composition prepared according to the method of claim 9, wherein, The amount of N-nitrosamine bumetanide impurities is less than 75 ppm over the shelf life of the pharmaceutical composition.

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