A nicorandil lyophilized preparation for injection and a method for preparing the same

Abstract

The application provides a nicorandil lyophilized preparation for injection and a preparation method thereof, and relates to the technical field of pharmaceutical preparations.The nicorandil lyophilized preparation for injection comprises an active ingredient nicorandil, D-alpha-tocopherol polyethylene glycol 1000 succinate and sodium citrate.The mass ratio of nicorandil to D-alpha-tocopherol polyethylene glycol 1000 succinate is 1:1-3, and the mass ratio of nicorandil to sodium citrate is 1-10:1.The preparation method can significantly improve the stability of the nicorandil lyophilized preparation for injection, realizes long-term storage at room temperature, and gets rid of the limitation of the existing product on cold chain.The preparation is quickly reconstituted, and the drug solution is clear, clear, free of visible foreign matters, free of opalescence and free of yellowing.D-alpha-tocopherol polyethylene glycol 1000 succinate micelles help nicorandil to be quickly dispersed and dissolved during reconstitution.The excipient D-alpha-tocopherol polyethylene glycol 1000 succinate micelles can realize the triple functions of antioxidation, physical isolation protection and solubilization, the prescription is simple, and the safety is good.

Description

Technical Field

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

[0002] Nicorandil, chemically known as N-(2-hydroxyethyl)nicotinamide nitrate, is the world's first antianginal drug with a dual mechanism of action of opening ATP-sensitive potassium channels and nitrate-like vasodilation. Its injectable formulation is used for the emergency treatment of unstable angina and acute myocardial infarction, and there is a large clinical demand for it.

[0003] However, the nitrate ester group (-ONO2) in nicotinic acid molecules is chemically unstable and readily undergoes hydrolysis and degradation in aqueous solutions, generating impurities such as N-(2-hydroxyethyl)nicotinamide and nicotinic acid, accompanied by the release of nitrate ions. The generation of nitrate ions lowers the solution pH, further accelerating the hydrolysis reaction and forming a positive feedback autocatalytic degradation cycle. Under heating or solid-state storage conditions, nicotinic acid can also undergo dimerization, generating dimer and trimer impurities. This inherent chemical instability leads to the following technical challenges: 1. Existing products require refrigerated storage at approximately 4°C, resulting in high cold chain transportation and storage costs, and limiting clinical use and patient accessibility. 2. Existing freeze-drying processes are complex. To address the adverse effects of the δ-crystal form formed when mannitol is used as an excipient on stability, patent EP2727593A1 proposes introducing an annealing step (heating the frozen product to -3°C to +3°C and holding for at least 40 minutes) during freeze-drying to inhibit the formation of the δ-mannitol crystal form. While this method improves room temperature stability to some extent, the annealing step significantly prolongs the freeze-drying cycle (adding 4-8 hours), increasing the complexity of process control and the risk of batch-to-batch variability, and placing higher demands on production equipment. Furthermore, even small deviations in annealing process parameters can lead to insufficient inhibition of δ-mannitol, affecting the consistency of batch-to-batch stability. 3. Existing antioxidant methods have limitations. Patent CN115381825A discloses vitamin C and butylated hydroxytoluene (BHT) as antioxidants, but vitamin C is unstable in aqueous solution and easily oxidizes and discolors, resulting in a yellowing of the solution after reconstitution; BHT has extremely poor water solubility, which may lead to visible foreign matter after reconstitution. Patent CN105287404A discloses monosodium glutamate and arginine as stabilizers, but their protective effect mainly comes from the pH buffering capacity of amino acids, which is insufficient for oxidative degradation. 4. Existing technologies lack "physical isolation" protection against nitrate hydrolysis. Whether it's a buffer salt system (sodium citrate), an amino acid system (arginine / monosodium glutamate), or an antioxidant system (VC / BHT), all only indirectly delay degradation by adjusting the microenvironment pH or scavenging free radicals; they cannot fundamentally prevent water molecules from nucleophilically attacking nitrate ester groups. 5. Existing products are inconvenient for clinical use. All marketed nicorandil injections are lyophilized powders for injection, requiring multiple steps before clinical use: "drawing solvent → injecting into vial → shaking to reconstitute → withdrawing syringe → changing needle → injection." In emergency and percutaneous coronary intervention scenarios, the reconstitution time directly affects the therapeutic effect. While some formulations improve long-term stability, they sacrifice reconstitution speed and the clarity of the reconstituted solution.

[0004] Therefore, there is an urgent need to develop an injectable nicorandil formulation that is simple to formulate, easy to process, can be stored at room temperature for a long time, and can be quickly reconstituted. Summary of the Invention

[0005] In view of this, the present invention proposes a lyophilized formulation of nicorandil for injection and its preparation method, thereby solving the above-mentioned problems. The technical solution of the present invention is implemented as follows: A lyophilized formulation of nicorandil for injection, characterized in that the formulation comprises the active ingredient nicorandil, D-α-tocopherol polyethylene glycol 1000 succinate, and sodium citrate; The mass ratio of nicorandil to D-α-tocopherol polyethylene glycol 1000 succinate is 1:1-3; The mass ratio of nicorandil to sodium citrate is 1-10:1.

[0006] Furthermore, the D-α-tocopherol polyethylene glycol 1000 succinate is used as a protective agent; and the sodium citrate is used as a pH adjuster.

[0007] A lyophilized formulation of nicorandil for injection, the formulation also includes the excipient trehalose.

[0008] A lyophilized formulation of nicorandil for injection, wherein the formulation is formulated for every 1000 vials as follows: Nicorandil 2-12g; D-α-Tocopherol Polyethylene Glycol 1000 Succinate 2-36g; Trehalose 3-18g; Sodium citrate 1.17-7g.

[0009] A method for preparing a lyophilized formulation of nicorandil for injection, comprising the following specific steps: (1) At 10-15°C and in the dark, add D-α-tocopherol polyethylene glycol 1000 succinate to 70wt%-80wt% of the formulation amount of water for injection and stir until completely dissolved to form a D-α-tocopherol polyethylene glycol 1000 succinate solution. (2) Add nicorandil to D-α-tocopherol polyethylene glycol 1000 succinate solution, stir to dissolve, and obtain drug solution; (3) Add trehalose to the drug solution and stir to dissolve. Then add sodium citrate, adjust the pH to 7.0-8.2, add the remaining water for injection, filter, fill into vials, and partially stopper to obtain the filled product; (4) The filled product is freeze-dried. After the freeze-drying is completed, nitrogen gas is added, the stopper is fully pressed, and the cap is crimped to obtain the target injectable nicorandil freeze-dried formulation.

[0010] Furthermore, in steps (1)-(3), the stirring speed is 80-150 rpm.

[0011] Furthermore, in step (4), the freeze-drying includes three stages: pre-freezing, sublimation drying, and desorption drying.

[0012] Furthermore, the pre-freezing is carried out at atmospheric pressure and at -50℃ to -40℃ for 3-5 hours.

[0013] Furthermore, the sublimation drying procedure is as follows: set temperature 5-10℃, set time 90min, hold time 200min, and control vacuum degree 0.2-0.3mbar.

[0014] Furthermore, the analytical drying procedure is as follows: set temperature 20-30℃, set time 60min, hold time 120min, and control vacuum degree 0.01-0.03mbar.

[0015] This invention uses D-α-tocopherol polyethylene glycol 1000 succinate as an excipient to achieve protection of nicorandil through the following mechanism: 1. Micellar Physical Isolation: During the preparation of D-α-tocopherol polyethylene glycol 1000 succinate, micelles are self-assembled in water. Nicorandil molecules spontaneously enter the hydrophobic core region of the D-α-tocopherol polyethylene glycol 1000 succinate micelles, where their nitrate ester groups are physically isolated from the aqueous phase by the hydrophobic shell of the micelles. Water molecules find it difficult to approach the nitrate ester groups for nucleophilic attack, thus slowing down the hydrolytic degradation reaction at its source. This effect continues in the drug solution stage before lyophilization and in the solution stage after reconstitution of the lyophilized product.

[0016] 2. Antioxidant properties of the Vitamin E group: The Vitamin E structure in the D-α-tocopherol polyethylene glycol 1000 succinate molecule can quench singlet oxygen, scavenge superoxide free radicals, and block the chain reaction of nitrate ester oxidation degradation initiated by free radicals, preventing nicorandil from discoloration and impurity growth due to oxidation. The thermal and chemical stability of D-α-tocopherol polyethylene glycol 1000 succinate is significantly better than that of free Vitamin C or butylated hydroxytoluene.

[0017] 3. Solubilization and dispersibility enhancement: D-α-tocopherol polyethylene glycol 1000 succinate has a high hydrophilic-lipophilic balance value (HLB≈13), which can accelerate the dissolution and dispersion of nicorandil during the reconstitution of lyophilized products, improve the reconstitution speed and the clarity of the reconstituted solution.

[0018] The synergistic effect of the above three mechanisms enables the formulation of the present invention to effectively protect nicorandil in both solid storage and reconstituted solution states, achieving long-term stable storage at room temperature without relying on complex freeze-drying and annealing processes.

[0019] Compared with the prior art, the beneficial effects of the present invention are: (1) The preparation method of the present invention can significantly improve the stability of lyophilized nicorandil for injection, achieve long-term storage at room temperature, and get rid of the limitation of existing products relying on cold chain.

[0020] (2) The freeze-drying process of the present invention is simplified, eliminating the need for an annealing step. Trehalose is used instead of mannitol as an excipient, shortening the freeze-drying cycle, reducing process steps, and lowering equipment requirements and production costs.

[0021] (3) The formulation of the present invention is rapidly reconstituted, and the drug solution is clear. After reconstitution, the drug solution is clear, free of visible foreign matter, opalescence, and yellowing. D-α-tocopherol polyethylene glycol 1000 succinate micelles help nicorandil disperse and dissolve rapidly during reconstitution, while avoiding the problems of insufficient dissolution and visible foreign matter that may be caused by using lipid-soluble antioxidants (such as BHT) alone.

[0022] (4) The formulation of the present invention has a simple formula and good safety. The excipient D-α-tocopherol polyethylene glycol 1000 succinate micelles of the present invention can simultaneously achieve the triple functions of anti-oxidation, physical isolation protection and solubilization, replacing the functions that need to be achieved by multiple excipients in conventional formulations, and the formulation composition is simple. Detailed Implementation

[0023] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.

[0024] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0025] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0026] The D-α-tocopherol polyethylene glycol 1000 succinate of this invention was purchased from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0027] Example 1 A lyophilized formulation of nicorandil for injection, with the following composition:

[0028] Preparation method: (1) At 10°C and in the dark, add D-α-tocopherol polyethylene glycol 1000 succinate to 4200 mL of water for injection and stir at 80 rpm until completely dissolved to form D-α-tocopherol polyethylene glycol 1000 succinate solution. (2) Add nicorandil to the D-α-tocopherol polyethylene glycol 1000 succinate solution and stir at 80 rpm to dissolve, to obtain the drug solution; (3) Add trehalose to the drug solution, stir at 80 rpm to dissolve, add sodium citrate, adjust the pH to 7.1±0.1, add water for injection to 6000 mL, filter, fill into vials, half-stop, and obtain the filled product; (4) The filling product is pre-frozen at normal pressure, followed by sublimation drying and desorption drying. After the freeze-drying is completed, nitrogen gas is introduced, the product is fully capped, and the target injectable nicorandil freeze-dried formulation is obtained.

[0029] Pre-freezing was performed at -50℃ for 3 hours. The sublimation drying procedure was set at 5℃ for 90 minutes, held for 200 minutes, and controlled at a vacuum of 0.2 mbar. The desorption drying procedure was set at 20℃ for 60 minutes, held for 120 minutes, and controlled at a vacuum of 0.01 mbar.

[0030] Example 2 A lyophilized formulation of nicorandil for injection, with the following composition:

[0031] Preparation method: (1) At 15°C and in the dark, add D-α-tocopherol polyethylene glycol 1000 succinate to 4800 mL of water for injection and stir at 150 rpm until completely dissolved to form a D-α-tocopherol polyethylene glycol 1000 succinate solution. (2) Add nicorandil to the D-α-tocopherol polyethylene glycol 1000 succinate solution and stir at 150 rpm to dissolve, to obtain the drug solution; (3) Add trehalose to the drug solution, stir and dissolve at 150 rpm, add sodium citrate, adjust the pH to 8.1±0.1, add water for injection to 6000 mL, filter, fill into vials, half-stop, and obtain the filled product; (4) The filling product is pre-frozen at normal pressure, followed by sublimation drying and desorption drying. After the freeze-drying is completed, nitrogen gas is introduced, the product is fully capped, and the target injectable nicorandil freeze-dried formulation is obtained.

[0032] Pre-freezing was performed at -40℃ for 5 hours. The sublimation drying procedure was set at 10℃ for 90 minutes, held for 200 minutes, and controlled at a vacuum of 0.3 mbar. The desorption drying procedure was set at 30℃ for 60 minutes, held for 120 minutes, and controlled at a vacuum of 0.03 mbar.

[0033] Example 3 A lyophilized formulation of nicorandil for injection, with the following composition:

[0034] Preparation method: (1) At 12°C and in the dark, add D-α-tocopherol polyethylene glycol 1000 succinate to 4500 mL of water for injection and stir at 100 rpm until completely dissolved to form D-α-tocopherol polyethylene glycol 1000 succinate solution. (2) Add nicorandil to the D-α-tocopherol polyethylene glycol 1000 succinate solution and stir at 100 rpm to dissolve, to obtain the drug solution; (3) Add trehalose to the drug solution, stir at 100 rpm to dissolve, add sodium citrate, adjust the pH to 7.5±0.1, add water for injection to 6000 mL, filter, fill into vials, half-stop, and obtain the filled product; (4) The filling product is pre-frozen at normal pressure, followed by sublimation drying and desorption drying. After the freeze-drying is completed, nitrogen gas is introduced, the product is fully capped, and the target injectable nicorandil freeze-dried formulation is obtained.

[0035] Pre-freezing was performed at -45℃ for 4 hours. The sublimation drying procedure was set at 8℃ for 90 minutes, held for 200 minutes, and controlled at a vacuum of 0.25 mbar. The desorption drying procedure was set at 25℃ for 60 minutes, held for 120 minutes, and controlled at a vacuum of 0.02 mbar.

[0036] Comparative Example 1 The difference from Example 3 is that trehalose is replaced with mannitol, and freeze-drying is carried out according to the freeze-drying method of CN115950213A. Otherwise, it is the same as Example 1.

[0037] Comparative Example 2 The difference from Example 3 is that D-α-tocopherol polyethylene glycol 1000 succinate is missing; otherwise, it is the same as Example 1.

[0038] The comparative example of lyophilized nicorandil for injection was prepared by the following methods: (1) Take 4500mL of water for injection, control the water temperature at 12°C, add sodium citrate and trehalose, stir at 100rpm until completely dissolved, then add nicorandil, stir at 100rpm until completely dissolved, add water for injection to 6000mL, filter, fill into vials, half-stop, and obtain the filled product. (2) The filling product is pre-frozen at normal pressure, followed by sublimation drying and desorption drying. After the freeze-drying is completed, nitrogen gas is introduced, the product is fully capped, and the target injectable nicorandil freeze-dried formulation is obtained.

[0039] Pre-freezing was performed at -45℃ for 4 hours. The sublimation drying procedure was set at 8℃ for 90 minutes, held for 200 minutes, and controlled at a vacuum of 0.25 mbar. The desorption drying procedure was set at 25℃ for 60 minutes, held for 120 minutes, and controlled at a vacuum of 0.02 mbar.

[0040] Comparative Example 3 The difference from Example 3 is that the solution preparation temperature is 40°C, while the rest is the same as Example 1.

[0041] Comparative Example 4 Prepared according to the method in CN115381825A.

[0042] Comparative Example 5 Prepared according to the method in CN105287404A.

[0043] Test Example 1 The lyophilized nicorandil for injection prepared in Examples 1-3 and Comparative Examples 1-5 were tested for pH value, related substances, and total impurities. The results are shown in Table 1.

[0044] Among them, the relevant substances include impurity C (nicorandil EP impurity C, CAS: 88598-33-8), impurity D (nicorandil EP impurity D, CAS: 40055-37-6) and dimer (nicorandil dimer, CAS: 2250142-73-3).

[0045] The chromatographic conditions for detecting impurities C, D, and dimers were as follows: high-performance liquid chromatography (HPLC) was used, with octadecylsilane-bonded silica gel as the stationary phase (4.6 mm × 250 mm, 5 μm), and water was used as the solvent. Trifluoroacetic acid Triethylamine Tetrahydrofuran (982:3:5:10) was used as the mobile phase for isocratic elution. The column temperature was 23°C, the detection wavelength was 254 nm, the flow rate was 1.0 ml / min, and the injection volume was 10 μl.

[0046] The results are shown in Table 1.

[0047] Table 1

[0048] As can be seen from Table 1, the related substances of the lyophilized nicorandil injection preparations prepared in Examples 1-3 of this invention are lower than those in Comparative Examples 1-5, the total impurities are lower than those in Comparative Examples 1-5, and the content and pH value meet the requirements.

[0049] Test Example 2 Six vials each of the lyophilized nicorandil for injection prepared in Examples 1-3 and Comparative Examples 1-5 were injected with 5 mL of water for injection using a syringe. The solution was manually shaken (approximately 2 times / second). The time from the start of water injection until the lyophilized powder was completely dissolved and the solution became clear and transparent was recorded. The average value of the six vials was taken as the reconstitution time. The results are shown in Table 2.

[0050] Table 2

[0051] As can be seen from Table 2, the reconstitution time of the lyophilized nicorandil injection preparations prepared in Examples 1-3 of the present invention is shorter than that of Comparative Examples 1-5, indicating that the D-α-tocopherol polyethylene glycol 1000 succinate micelle system of the present invention can accelerate the dispersion and dissolution of nicorandil during reconstitution and has a good solubilizing effect.

[0052] Test Example 3 The stability of the lyophilized nicorandil for injection prepared in Examples 1-3 and the commercially available lyophilized nicorandil for injection (purchased from Beijing Sihuan Kebo Pharmaceutical Co., Ltd.) was investigated. 1. Improve stability The lyophilized nicorandil injectable formulation to be tested was placed at 40℃±2℃ and RH70%±5% for 6 months. Samples were taken at the end of the 1st, 3rd and 6th months during the test period to detect related substances and total impurities. The results are shown in Table 3.

[0053] Table 3

[0054] 2. Long-term stability The lyophilized nicorandil injectable formulation to be tested was sampled at 0, 12 and 24 months under the conditions of temperature 25°C±2°C and relative humidity 60%±5%, and the contents of related substances and total impurities were detected. The results are shown in Table 4.

[0055] Table 4

[0056] As can be seen from Tables 3-4, under accelerated testing conditions (temperature 40°C±2°C, relative humidity 70%±5%) for 6 months and under long-term testing conditions (temperature 25°C±2°C, relative humidity 60%±5%) for 24 months, the related substances, total impurities and contents of the formulations of Examples 1-3 of this invention all meet the requirements, and the stability is good.

[0057] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A lyophilized formulation of nicorandil for injection, characterized in that, The formulation includes the active ingredient nicorandil, D-α-tocopherol polyethylene glycol 1000 succinate, and sodium citrate; The mass ratio of nicorandil to D-α-tocopherol polyethylene glycol 1000 succinate is 1:1-3; The mass ratio of nicorandil to sodium citrate is 1-10:

1.

2. The lyophilized formulation of nicorandil for injection as described in claim 1, characterized in that, The D-α-tocopherol polyethylene glycol 1000 succinate is used as a protective agent; the sodium citrate is used as a pH adjuster.

3. A lyophilized formulation of nicorandil for injection as described in claim 1 or 2, characterized in that, The formulation also includes the excipient trehalose.

4. The lyophilized formulation of nicorandil for injection as described in claim 3, characterized in that, The formulation for each 1000 vials of the above preparation is as follows: Nicorandil 2-12g; D-α-Tocopherol Polyethylene Glycol 1000 Succinate 2-36g; Trehalose 3-18g; Sodium citrate 1.17-7g.

5. The method for preparing a lyophilized formulation of nicorandil for injection according to claim 4, characterized in that, The specific preparation steps include: (1) At 10-15°C and in the dark, add D-α-tocopherol polyethylene glycol 1000 succinate to 70wt%-80wt% of the formulation amount of water for injection and stir until completely dissolved to form a D-α-tocopherol polyethylene glycol 1000 succinate solution. (2) Add nicorandil to D-α-tocopherol polyethylene glycol 1000 succinate solution, stir to dissolve, and obtain drug solution; (3) After adding trehalose to the drug solution and stirring to dissolve it, add sodium citrate, adjust the pH to 7.0-8.2, add the remaining water for injection, filter, fill, and partially stopper to obtain the filled product; (4) The filled product is freeze-dried. After the freeze-drying is completed, nitrogen gas is added, the stopper is fully pressed, and the cap is crimped to obtain the target injectable nicorandil freeze-dried formulation.

6. The method for preparing a lyophilized formulation of nicorandil for injection as described in claim 5, characterized in that, In steps (1)-(3), the stirring speed is 80-150 rpm.

7. The method for preparing a lyophilized formulation of nicorandil for injection as described in claim 5, characterized in that, In step (4), the freeze drying includes three stages: pre-freezing, sublimation drying, and desorption drying.

8. The method for preparing a lyophilized formulation of nicorandil for injection as described in claim 7, characterized in that, The pre-freezing process involves pre-freezing at -50℃ to -40℃ for 3-5 hours under normal pressure.

9. The method for preparing a lyophilized formulation of nicorandil for injection as described in claim 7, characterized in that, The sublimation drying procedure is as follows: set temperature 5-10℃, set time 90min, hold time 200min, and control vacuum degree 0.2-0.3mbar.

10. The method for preparing a lyophilized formulation of nicorandil for injection as described in claim 7, characterized in that, The analytical drying procedure is as follows: set temperature 20-30℃, set time 60min, hold time 120min, and control vacuum degree 0.01-0.03mbar.

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