A method for preparing a nicorandil lyophilized preparation for injection

Abstract

This invention discloses a method for preparing a lyophilized nicorandil injection formulation, comprising the following steps: S1: Preparation of the solution: Mannitol and sodium citrate are added to water for injection at 2-8°C and stirred to dissolve. Nicorandil is then added and stirred until the solution is clear. The pH is adjusted to 7.4-7.9 with citric acid solution to obtain the solution; S2: Filtration: The solution is filtered to obtain the drug solution; S3: Filling: The drug solution is filled into vials, partially stoppered, and placed in a lyophilizer cooled to 5°C; S4: Lyophilization; S5: Unpacking and capping. The lyophilized nicorandil injection formulation prepared by this method has the advantages of high stability, short cycle time, and low production cost.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical formulation technology, and in particular to a method for preparing a lyophilized formulation of nicorandil for injection. Background Technology

[0002] Nicorandil, chemically named N-(2-hydroxyethyl)nicotinamide nitrate, has the following structural formula:

[0003]

[0004] Nicorandil is a K+ channel opener with nitrate-like effects. In patients with stable angina, and even vasospastic angina, it can relieve symptoms to a similar degree as nitrates, beta-blockers, and calcium channel antagonists. The opening of mitochondrial K+ channels induced by nicorandil can protect cardiomyocytes and reduce cardiovascular events. Therefore, it can both relieve angina symptoms and improve prognosis, thus reducing the incidence of cardiovascular events. Consequently, nicorandil is an ideal antianginal drug.

[0005] Nicorandil for injection was first marketed in Japan (trade name Sigmart). In the 26th batch of reference preparations released by the National Medical Products Administration, Sigmart was designated as a reference preparation.

[0006] Because nicorandil has a nitrate ester structure, it is easily hydrolyzed and polymerized under thermal conditions, leading to instability in lyophilized nicorandil formulations. During research, it was frequently observed that the impurity content of commercially available products gradually increases during storage, with nitrate ions (NO3-) being the primary impurity detected. - Impurities B, D, and F (nicorandil dimer) have the following structures:

[0007] Impurity B:

[0008]

[0009] Impurity D:

[0010]

[0011] Impurity F (nicorandil dimer):

[0012]

[0013] Methods for preparing injectable nicorandil have been reported, and existing methods describe both the formulation and the manufacturing process. Early methods essentially only provided simple formulations and processes to produce the product, while later methods mainly focused on improving the formulation and process to enhance the stability of injectable nicorandil.

[0014] US4200640 discloses a method for preparing a lyophilized formulation of nicorandil, the formulation of which is nicorandil and mannitol. Lyophilization parameters are not reported. (See EXAMPLE 7e)

[0015] US4769381 discloses a method for preparing a lyophilized formulation of nicorandil, the formulation of which is nicorandil, sodium citrate, and mannitol. Lyophilization parameters are not reported. (See EXAMPLE 1)

[0016] CN200610041778.2 (Authorization Announcement No. CN100417381C) discloses a method for preparing a lyophilized nicorandil formulation: its formula consists of nicorandil, L-serine, and sodium bisulfite. Lyophilization parameters are not reported.

[0017] CN200910076907.5 (Authorization Announcement No. CN101474161B) discloses a method for preparing nicorandil for injection: its formula is nicorandil, mannitol, and sodium citrate (Example 1). The freeze-drying procedure is shown in Table 1 (Example 1).

[0018] Table 1:

[0019]

[0020]

[0021] Note: This freeze-drying procedure table is obtained by tabulating the content of the patent report. The same applies below.

[0022] CN201280042326.X (Publication No. CN103764146A) discloses a method for preparing a lyophilized nicorandil formulation: the formulation consists of nicorandil, D-mannitol, and sodium citrate. The lyophilization method reports an annealing operation during the pre-freezing stage: first pre-freezing at -40℃, then heating to 0℃ for two 6-hour cycles.

[0023] (Example 1)

[0024] CN201510698037.0 (Authorization Announcement No. CN105287404B) discloses a method for preparing a lyophilized nicorandil formulation: its formula consists of nicorandil, lactose, sodium citrate, and citric acid (Examples 5 and 6), and the solvent is ethanol. The lyophilization procedure is shown in Table 2 (Example 11).

[0025] Table 2:

[0026]

[0027] CN201711192270.7 (Publication No. CN108078930A) discloses a method for preparing nicorandil for injection: its formulation consists of nicorandil, mannitol, and sodium citrate (Example 1). The freeze-drying procedure is shown in Table 3 (Example 1).

[0028] Table 3:

[0029]

[0030]

[0031] CN202110268261.1 (Authorization Announcement No. CN113599353B) discloses a method for preparing nicorandil for injection: its formula consists of nicorandil, mannitol, sodium citrate, and citric acid (pH adjuster). The freeze-drying procedure is shown in Table 4.

[0032] Table 4:

[0033]

[0034] CN202210007149.7 (Publication No. CN115300465A) discloses a method for preparing nicorandil for injection: its formula consists of nicorandil, mannitol, and sodium citrate. The freeze-drying procedure is shown in Table 5 (Example 1).

[0035] Table 5:

[0036]

[0037] CN202210174923.3 (Publication No. CN114601806A) discloses a method for preparing nicorandil for injection: its formulation consists of nicorandil, mannitol, and sodium citrate. The freeze-drying procedure is shown in Table 6 (see rows 0157 and 0158).

[0038] Table 6:

[0039]

[0040] CN202211062847.3 (Publication No. CN115381825A) discloses a method for preparing nicorandil for injection: its formula consists of nicorandil, mannitol, vitamin C, and butylated hydroxytoluene. The lyophilization procedure is shown in Table 7.

[0041] Table 7:

[0042]

[0043] CN202211143596.1 (Publication No. CN115624527A) discloses a method for preparing nicorandil for injection: its formulation consists of nicorandil, sulfobutyl β-cyclodextrin, sarcosine, propyl gallate, and sodium citrate. The lyophilization procedure is shown in Table 8.

[0044] Table 8:

[0045]

[0046] CN202211267560.4 (Publication No. CN115487156A) discloses a method for preparing nicorandil for injection: its formulation consists of nicorandil, mannitol, maltodextrin, and sodium 2,3-dihydroxysuccinate (pH adjuster). Lyophilization parameters are not reported.

[0047] CN202211433449.8 (Publication No. CN115745879A) discloses a method for preparing nicorandil for injection: its formula consists of nicorandil, mannitol, and sodium citrate. The freeze-drying procedure is shown in Table 9.

[0048] Table 9:

[0049]

[0050] CN202211636515.1 (Publication No. CN115950213A) discloses a method for preparing nicorandil for injection: its formulation consists of nicorandil, mannitol, sodium citrate, and citric acid (pH adjuster). The lyophilization procedure is shown in Table 10.

[0051] Table 10:

[0052]

[0053] The nicorandil for injection reported in the existing technology are all lyophilized powder injections. Their dosage form, route of administration and indications are the same as Sigmart. According to the new registration classification requirements for chemical drugs, they should be classified as Class 3 or Class 4 chemical drugs, that is, generic drugs.

[0054] In China, there are strict restrictions on the prescription of generic injectable drugs. The "Technical Requirements for Consistency Evaluation of Quality and Efficacy of Generic Chemical Injectable Drugs" clearly stipulates that the types and amounts of excipients in injectable drugs should generally be the same as those in the reference preparation.

[0055] Information obtained from sources including, but not limited to, publicly available information on the reference formulation indicates that the reference formulation consists of nicorandil, mannitol, sodium citrate, and a pH adjuster. Among the publicly reported methods for preparing injectable nicorandil, those reported in CN200610041778.2, CN201510698037.0, CN202211062847.3, CN202211143596.1, and CN202211267560.4 have formulations inconsistent with the reference formulation, do not meet current technical guidance requirements, and lack practicality. Furthermore, other patents report methods for preparing injectable nicorandil, primarily focusing on the lyophilization process.

[0056] Freeze-drying technology is widely used in the food, pharmaceutical, and biological products industries to improve product stability and extend shelf life. A typical freeze-drying process includes the following steps:

[0057] Pre-freezing: Freezing the solution at a certain rate.

[0058] Single drying (single sublimation): Start vacuuming and gradually increase the temperature to sublimate the water until the water marks disappear or the product temperature is parallel to the plate temperature.

[0059] Secondary drying (analytical drying): The plate temperature and vacuum level are further increased and maintained for a period of time to remove residual moisture.

[0060] To further improve the stability of nicorandil lyophilized formulations, existing technologies employ some special operations based on typical lyophilization processes. For example, CN201280042326.X and CN201711192270.7 perform annealing during the pre-freezing stage; CN202110268261.1 uses a combination of freeze-thaw and annealing operations during the pre-freezing stage; and CN202211636515.1 performs annealing during both the pre-freezing and secondary drying stages.

[0061] While existing technologies can indeed improve the stability of injectable nicorandil compared to traditional freeze-drying processes, they still exhibit some shortcomings. CN201280042326.X and CN201711192270.7 only involve special treatment during the pre-freezing stage, and the product stability is insufficient to reach the same level as the reference formulation.

[0062] CN202110268261.1 and CN202211636515.1 used two special operations in the freeze-drying process, which extended the freeze-drying cycle and increased production costs. Under the background of centralized drug procurement to reduce costs and increase efficiency, this is not conducive to the formation of pharmaceutical companies' competitiveness. Summary of the Invention

[0063] In view of the shortcomings of the prior art, the technical problem to be solved by this patent application is how to provide a method for preparing a lyophilized nicorandil injectable formulation with high stability, short cycle time and low production cost.

[0064] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0065] A method for preparing a lyophilized formulation of nicorandil for injection includes the following steps:

[0066] S1: Preparation of the solution: Add mannitol and sodium citrate to water for injection at 2-8℃, stir to dissolve, then add nicorandil, stir to dissolve until the solution is clear, adjust the pH to 7.4-7.9 with citric acid solution to obtain the solution;

[0067] S2: Filtration: Filter the solution to obtain the drug solution;

[0068] S3: Filling: Fill the vials with the liquid medicine, partially stopper them, and place them in a freeze dryer that has been cooled to 5°C;

[0069] S4: Freeze-dried;

[0070] S5: Unpacking and capping.

[0071] In step S1, the solution is prepared from nicorandil, mannitol, sodium citrate, and water for injection, with the following weight ratios for each component:

[0072] Nicorandil: Mannitol: Sodium citrate: Water for injection = 2:3:1:1000~3000.

[0073] In step S2, the filtration process is as follows: the solution is filtered and sterilized sequentially through a 0.45μm filter and a 0.22μm filter.

[0074] In step S3, during filling, 1-3 ml of the drug solution is taken and filled into a 7 ml vial.

[0075] In step S4, freeze drying includes the following steps:

[0076] P1: Pre-freezing: Set the temperature below -40℃ and maintain it for more than 2 hours;

[0077] P2: Annealing: Set the temperature to -2 to 2℃ and hold for 2 to 4 hours; slowly cool down to below -40℃ and hold for more than 2 hours;

[0078] P3: First drying;

[0079] P4: Secondary drying: Set the temperature to 10-30℃, and control the vacuum degree to 0-15Pa, and maintain for 5-10 hours.

[0080] In step P3, during the first drying, the temperature is set to -13 to 0°C, while the vacuum degree is controlled at 200 to 600 Pa and maintained for 1 to 3 hours; the vacuum degree is controlled at 30 to 100 Pa and maintained for 1 to 3 hours; the vacuum degree is controlled at 200 to 600 Pa again and maintained for 1 to 3 hours; the vacuum degree is controlled at 30 to 100 Pa again and maintained for 1 to 3 hours.

[0081] Preferably, in step P3, during the first drying, the temperature is set to -5 to 0°C, while the vacuum degree is controlled at 200 to 400 Pa, and maintained for 7 to 9 hours.

[0082] In summary, the lyophilized nicorandil for injection prepared by this method has the advantages of high stability, short production cycle, and low production cost. Attached Figure Description

[0083] Figure 1 Test diagram for determining the eutectic point of the drug solution in step S2 using the resistance method;

[0084] Figure 2 This is a diagram showing the state of the freeze dryer and the product during the freeze-drying process in Embodiment 1 of the present invention.

[0085] Figure 3 This is a diagram showing the state of the freeze dryer and the product during the freeze-drying process in Embodiment 2 of the present invention.

[0086] Figure 4 This is a diagram showing the state of the freeze dryer and the product during the freeze-drying process in Embodiment 3 of the present invention.

[0087] Figure 5 This is a diagram showing the state of the freeze dryer and the product during the freeze-drying process in Embodiment 4 of the present invention.

[0088] Figure 6 The diagram shown is a freeze dryer-product state diagram during the freeze drying process of Comparative Example 1 of the present invention.

[0089] Figure 7 The diagram shown is a freeze dryer-product state diagram during the freeze drying process of Comparative Example 2 of the present invention.

[0090] Figure 8 The diagram shown is a freeze dryer-product state diagram during the freeze drying process of Comparative Example 3 of the present invention.

[0091] Figure 9 The figure shown is the HPLC detection chromatogram of Example 1 "3 months at 25°C";

[0092] Figure 10 The figure shown is the HPLC detection chromatogram of Example 2, "3 months at 25°C";

[0093] Figure 11 The figure shown is the HPLC detection chromatogram of Example 3 "3 months at 25°C";

[0094] Figure 12 The figure shown is the HPLC detection chromatogram of Example 4, "3 months at 25°C";

[0095] Figure 13 The figure shown is the HPLC detection chromatogram of Comparative Example 1 "3 months at 25℃".

[0096] Figure 14 The figure shown is the HPLC detection chromatogram of Comparative Example 2, "3 months at 25℃".

[0097] Figure 15 The figure shown is the HPLC detection chromatogram of Comparative Example 3 "at 25℃ for 3 months". Detailed Implementation

[0098] The present invention will now be described in further detail with reference to the accompanying drawings.

[0099] A method for preparing a lyophilized formulation of nicorandil for injection includes the following steps:

[0100] S1: Preparation of the solution: Weigh 3.6g mannitol and 1.2g sodium citrate, add them to water for injection at 2-8℃, stir to dissolve, then add 2.4g nicorandil, stir to dissolve until the solution is clear, adjust the pH to 7.4-7.9 with citric acid solution to obtain the solution;

[0101] S2: Filtration: The solution is filtered and sterilized by passing it through a 0.45μm filter and a 0.22μm filter in sequence to obtain the drug solution ready for filling;

[0102] S3: Filling: Take 3ml of the medicine solution, fill it into a 7ml vial, stopper it halfway, and put it into a freeze dryer that has been cooled to 5℃;

[0103] S4: Freeze-drying; the freeze-drying parameters are specific to this invention and will be described below in conjunction with specific embodiments.

[0104] S5: Unpacking and capping.

[0105] When implemented, freeze drying includes the following steps:

[0106] P1: Pre-freezing: Set the temperature below -40℃ and maintain it for more than 2 hours;

[0107] P2: Annealing: Set the temperature to -2 to 2℃ and hold for 2 to 4 hours; slowly cool down to below -40℃ and hold for more than 2 hours;

[0108] P3: First drying;

[0109] P4: Secondary drying: Set the temperature to 10-30℃, and control the vacuum degree to 0-15Pa, and maintain for 5-10 hours.

[0110] Specifically, in step P3, during the first drying, the temperature is set to -13 to 0°C, while the vacuum degree is controlled at 200 to 600 Pa, and maintained for 1 to 3 hours; the vacuum degree is controlled at 30 to 100 Pa, and maintained for 1 to 3 hours; the vacuum degree is controlled at 200 to 600 Pa again, and maintained for 1 to 3 hours; the vacuum degree is controlled at 30 to 100 Pa again, and maintained for 1 to 3 hours.

[0111] Specifically, in step P3, during the first drying, the temperature is set to -5 to 0°C, while the vacuum degree is controlled at 200 to 400 Pa, and maintained for 7 to 9 hours.

[0112] The drying parameters were creatively proposed and optimized based on considerations of the annealing operation in existing technologies, and these parameters produced the desired effect. Existing technologies involve annealing during pre-freezing. Regarding the annealing mechanism, it is generally believed that the solute recrystallizes during annealing, thus altering its properties. Regarding freeze-drying annealing operations, current literature almost exclusively reports on annealing during the pre-freezing stage. Annealing requires raising the product temperature (material temperature) above the eutectic point, followed by cooling to achieve recrystallization. The eutectic point of the drug solution during preparation was determined using the resistance method, and the result was -15℃. The test graph is shown below. Figure 1 .

[0113] The primary drying process involves the gradual sublimation and escape of water from the system under a frozen state and high vacuum. This primary drying process is similar to the pre-freezing process, as the system is in a frozen state. Annealing during the primary sublimation process can produce a similar effect to annealing during the pre-freezing stage, namely, improving the stability of the product. This was verified through a series of experiments, resulting in the aforementioned primary drying parameters.

[0114] Example 1, see Figure 2 and Figure 9 ;

[0115] The complete freeze-drying parameters used in Example 1 are shown in Table 11.

[0116] Table 11:

[0117]

[0118]

[0119] Examples 2-4, see Figure 3-5 as well as Figure 10-12 ;

[0120] The complete freeze-drying parameters used in Examples 2-4 are shown in Table 12.

[0121] Table 12:

[0122]

[0123]

[0124] Comparative Example 1, see Figure 6 and Figure 13 ;

[0125] The complete freeze-drying parameters used in Comparative Example 1 are shown in Table 13.

[0126] Table 13:

[0127]

[0128]

[0129] Comparative Example 2, see Figure 7 and Figure 14 ;

[0130] The complete freeze-drying parameters used in Comparative Example 2 are shown in Table 14.

[0131] Table 14:

[0132]

[0133]

[0134] Comparative Example 3, see Figure 8 and Figure 15 ;

[0135] The complete freeze-drying parameters used in Comparative Example 3 are shown in Table 15.

[0136] Table 15:

[0137]

[0138]

[0139] Experiment 1: Comparative study of annealing and non-annealing in a single drying stage, see Table 16.

[0140] Table 16:

[0141]

[0142] Unlike the pre-freezing process, which controls the material temperature by raising and lowering the temperature plate to achieve annealing, the annealing process in this embodiment fully utilizes the "temperature-saturated vapor pressure" curve of ice during the primary drying process. By controlling the vacuum level, the material temperature is controlled, achieving the heating and cooling process of the material, thereby realizing the annealing process. The "temperature-saturated vapor pressure" relationship of ice is shown in Table 17.

[0143] Table 17:

[0144] Temperature ℃ pressure Pa Temperature ℃ pressure Pa Temperature ℃ pressure Pa -36 20.1 -19 113.3 -9 283.3 -34 24.9 -18 124.6 -8 309.4 -32 30.9 -17 136.9 -7 377.6 -30 38.4 -16 150.4 -6 368.1 -28 47.1 -15 165 -5 401 -26 57.2 -14 180.9 -4 436.8 -24 70.1 -13 198.1 -3 475.4 -22 85.8 -12 216.9 -2 517.2 -21 94.4 -11 237.3 -1 562.1 -20 102.9 -10 259.4 0 610

[0145] In the experimental example, the material temperature corresponding to 400 Pa is about -5℃, which is higher than the eutectic point, and the material temperature corresponding to 30 Pa is about -32℃, which is lower than the eutectic point.

[0146] The stability of the experimental samples at 25℃ (Note: the storage conditions for nicorandil for injection are 2-8℃, and 25℃ is the accelerated storage condition) are shown in Table 18.

[0147] Table 18:

[0148]

[0149]

[0150] Note: Because the degradation process of this product generates impurities B, D, and F, nitrate ions are produced. To avoid double counting, nitrate ions are not included in the total impurities. The same applies below.

[0151] The results showed that the nitrate and total impurities were significantly lower in the accelerated drying and annealing process during the first drying and annealing process in March, indicating that the first drying and annealing process can significantly improve product stability.

[0152] Experiment 2: Simplifying the parameters for a single drying step

[0153] While there are similarities between single-stage drying annealing and pre-freezing annealing, there are also differences. Specifically, the recrystallization process in pre-freezing annealing can only be achieved by lowering the temperature, while in single-stage drying, the moisture content is continuously reduced. In addition to controlling the temperature to achieve recrystallization, recrystallization can also be achieved directly by reducing the moisture content. That is, the process of controlling the material temperature by adjusting the vacuum level in Example 1 may be unnecessary, as shown in Table 19.

[0154] Table 19:

[0155]

[0156]

[0157] The results of the stability test at 25℃ are shown in Table 20.

[0158] Table 20:

[0159]

[0160] The results showed that, after 3 months of accelerated drying, there was no difference in impurity size between Example 2 and Example 1, indicating that the single-drying method used in Example 2 had the same effect as that in Example 1. The control method in Example 2 is simpler and is the preferred solution.

[0161] Experiment 3: Investigating stability under different vacuum levels

[0162] Using the single-drying scheme employed in Example 2, a comparative study was conducted on different vacuum levels. The material temperatures corresponding to Example 4 and Comparative Example 1 were lower than the eutectic point, as shown in Table 21.

[0163] Table 21:

[0164]

[0165] The results of the stability test at 25℃ are shown in Table 22.

[0166] Table 22:

[0167]

[0168]

[0169] The results show that when the vacuum level is between 200 and 400 Pa (corresponding to a material temperature above the eutectic point), there is no difference in impurity size after 3 months of acceleration; the stability at 200–400 Pa is significantly higher than that at 30–100 Pa (corresponding to a material temperature below the eutectic point). The experiment confirms that when the selected vacuum level ensures that the material temperature is above the eutectic point, the product stability is significantly improved.

[0170] Experiment 4: Comparison of the present invention with existing technologies

[0171] The stability of the present invention at 25°C was examined by comparing it with the technologies described in CN202110268261.1 (Comparative Example 2) and CN202211636515.1 (Comparative Example 3), and the results are shown in Table 23.

[0172] Table 23:

[0173]

[0174]

[0175] The results show that the product stability corresponding to this invention is slightly better than CN202110268261.1 and significantly better than CN202211636515.1.

[0176] Furthermore, the freeze-drying cycle corresponding to this invention is about 40 hours, which is significantly shorter than the 60 hours in CN202110268261.1.

[0177] Therefore, the present invention has significant advantages over the prior art.

[0178] Detection example

[0179] This invention assesses the stability of each experimental example by detecting related substances after being placed at 25°C for 3 months. The specific detection methods involved are as follows:

[0180] (1) Chromatographic conditions

[0181] Chromatographic column: A chromatographic column packed with octadecylsilane-bonded silica gel Inertsustain C18 (250 mm × 4.6 mm, 5 μm);

[0182] Mobile phase A: 0.01 mol / L diammonium hydrogen phosphate solution: acetonitrile = 90:10 (adjust pH to 7.0 with phosphoric acid)

[0183] Mobile phase B: 0.01 mol / L diammonium hydrogen phosphate solution: acetonitrile = 70:30 (adjust pH to 7.0 with phosphoric acid)

[0184] Column temperature: 25℃

[0185] Flow rate: 1.0 ml / min

[0186] Detection wavelengths: 262nm, 215nm

[0187] Injection volume: 20 μl

[0188] Solvent: Mobile phase A

[0189] The runtime gradient is as follows:

[0190]

[0191] (2) Solution preparation

[0192] System suitability solution: Take appropriate amounts of nicotinic acid reference standard, nicotinic acid, impurity B, impurity C, impurity D, and impurity F reference standards, dissolve and dilute them in mobile phase A to prepare a mixed solution containing approximately 1 mg of nicotinic acid, approximately 2 μg each of nicotinic acid and impurity B, and approximately 4 μg each of impurities C, impurity D, and impurity F per 1 ml.

[0193] Nitrate reference solution: Take an appropriate amount of sodium nitrate, add mobile phase A to dissolve and dilute to prepare a solution containing approximately 8 μg of nitrate per 1 ml.

[0194] Test solution: Prepare fresh before use. Take 5 bottles of this product, dissolve and dilute with mobile phase A to prepare a solution containing approximately 1 mg of nicorandil per ml.

[0195] Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, add mobile phase A to dilute to the mark, and shake well.

[0196] (3) Measurement method

[0197] Accurately measure 20 μl each of the blank solution and system suitability solution, inject them into the liquid chromatograph, and record the chromatograms. In the chromatogram of the system suitability solution, the elution order is nicotinic acid, impurity C, impurity B, impurity F, impurity D, and nicorandil. The resolution between each impurity and the resolution between impurity D and nicorandil should meet the requirements. Accurately measure 20 μl each of the nitrate reference solution, the test solution, and the control solution, inject them into the liquid chromatograph, and record the chromatograms.

[0198] Finally, it should be noted that those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for preparing a lyophilized formulation of nicorandil for injection, characterized in that, Includes the following steps: S1: Preparation of the solution: Mannitol and sodium citrate are added to water for injection at 2-8°C and stirred to dissolve. Nicorandil is then added and stirred until the solution is clear. The pH is adjusted to 7.4-7.9 with citric acid solution to obtain the solution. The weight ratio of each component in the solution is nicorandil:mannitol:sodium citrate:water for injection = 2:3:1:1000-3000. S2: Filtration: The solution is filtered through a 0.45μm filter and a 0.22μm filter in sequence to remove bacteria, thus obtaining the drug solution; S3: Filling: Take 1-3 ml of the drug solution, fill it into a 7 ml vial, stopper it halfway, and put it into a freeze dryer that has been cooled to 5°C; S4: Freeze-drying: includes the following steps: P1: Pre-freezing: Set the temperature below -40℃ and maintain it for more than 2 hours; P2: Annealing: Set the temperature to -2~2℃ and hold for 2~4 hours; slowly cool down to below -40℃ and hold for more than 2 hours; P3: First drying: Set the temperature to -13~0℃, while controlling the vacuum degree to 200~600Pa, and maintain for 1~3 hours; control the vacuum degree to 30~100Pa, and maintain for 1~3 hours; control the vacuum degree to 200~600Pa again, and maintain for 1~3 hours; control the vacuum degree to 30~100Pa again, and maintain for 1~3 hours, or set the temperature to -5~0℃, while controlling the vacuum degree to 200~400Pa, and maintain for 7~9 hours; P4: Secondary drying: Set the temperature to 10~30℃, and control the vacuum degree to 0~15Pa, and maintain for 5~10 hours; S5: Unpacking and capping.

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