Nimodipine injection and preparation method thereof

Abstract

The invention discloses a nimodipine injection and a preparation method thereof. The nimodipine injection provided by the invention comprises pretreated polyethylene glycol 400; according to the pretreatment method, the temperature is increased to 100-160 DEG C through heating.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a nimodipine injection and a preparation method thereof. Background Art

[0002] Nimodipine is a second-generation dihydropyridine calcium antagonist. Because it is easy to penetrate the blood-brain barrier, it has the effects of selectively dilating cerebral blood vessels and significantly reversing the spasm of the basilar artery and anterior spinal artery. Clinically, it is used to treat hypertension, stroke, migraine, subarachnoid hemorrhage and other cerebral hemorrhage diseases. It is the first choice drug for cerebrovascular treatment at present, and has high clinical application value for senile dementia in particular. Nimodipine is a calcium antagonist with strong selectivity and cerebral vasodilating effect, which was launched by Bayer Vital GmbH in May 1985. It is well absorbed through the oral digestive tract, but has a large first-pass effect, and its bioavailability is only 2.7-27.9%.

[0003] In the 1990s, nimodipine injection for intravenous administration was developed for the prevention and treatment of neurological damage caused by cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Nimodipine injection is only marketed in Europe and China, with the trade name Nimotop, and the approved specification is 50mL:10mg. According to the information in the preparation instructions of various countries, nimodipine injection contains nimodipine, ethanol, polyethylene glycol 400, sodium citrate, anhydrous citric acid, and water for injection. The original research was first approved in Germany in 1985, and it was launched in China in 2004. Although nimodipine injection has been on the market for a long time, the applicant has found that the quality of currently marketed nimodipine injections varies greatly, especially there are obvious stability problems. Summary of the Invention

[0004] The property that nimodipine is insoluble in water greatly limits its clinical application. When preparing it into a liquid preparation for intravenous use, in order to avoid adverse consequences during the medication process, it is necessary to find a suitable method to increase its solubility. The currently marketed injections contain about 20% (V / V) ethanol and other excipients such as polyethylene glycol 400.

[0005] During the research process, the applicant found that the main reason for the large quality difference of nimodipine injections of different batches mentioned above is that the quality of the added excipient polyethylene glycol 400 varies greatly; in order to keep the impurities of nimodipine injection at a low level and meet the quality requirements, the present invention optimizes the pretreatment of polyethylene glycol 400.

[0006] The present invention provides a nimodipine injection, which comprises pretreated polyethylene glycol 400; the pretreatment method: heating the temperature to 100°C - 160°C.

[0007] In some specific embodiments, the temperature is 105°C - 155°C.

[0008] In some specific embodiments, the temperature is 125°C - 155°C; further, the temperature is 130 ± 5°C.

[0009] In some specific embodiments, the heating time is 30 - 120 min; further, it is 60 min.

[0010] In some specific embodiments, the pretreatment is: heating polyethylene glycol 400 alone to a specific temperature, and the specific temperature is selected from 100°C - 160°C, specifically 105°C - 155°C, preferably 125°C - 155°C, more preferably 130 ± 5°C.

[0011] In some specific embodiments, the pretreatment is: heating to a specific temperature under a nitrogen-filled environment, and the nitrogen filling controls the dissolved oxygen ≤ 1.0 mg / L; the specific temperature is selected from 100°C - 160°C, specifically 105°C - 155°C, preferably 125°C - 155°C, more preferably 130 ± 5°C.

[0012] The applicant surprisingly found that for the polyethylene glycol 400 pretreated according to the present invention, the trace reducing substances thereof are further reduced, which has a very great improvement in enhancing the quality of the nimodipine injection; and heating polyethylene glycol to a specific temperature under a nitrogen-filled environment is more conducive to ensuring the stability of the injection, and will not cause the solvent to turn yellow or other possible additional problems such as high-temperature oxidation.

[0013] In the present invention, the nimodipine injection comprises: nimodipine, polyethylene glycol 400, ethanol, citric acid, sodium citrate, and water for injection.

[0014] In some embodiments of the present invention, the formulation of the nimodipine injection is: nimodipine, polyethylene glycol 400, ethanol, citric acid, sodium citrate, and the balance is water for injection.

[0015] In some specific embodiments, in the nimodipine injection, by weight percentage, nimodipine is 0.01% - 0.4%, polyethylene glycol 400 is 15% - 40%, ethanol is 15% - 30%, citric acid is 0.01% - 0.06%, sodium citrate is 0.15% - 0.5%, and water for injection is 30% - 70%.

[0016] In some specific embodiments, in the nimodipine injection, by weight percentage, nimodipine is 0.01% - 0.4%, polyethylene glycol 400 is 17% - 30%, ethanol is 15% - 22%, citric acid is 0.02% - 0.05%, sodium citrate is 0.18% - 0.3%, and water for injection is 45% - 70%.

[0017] In some specific embodiments, in the nimodipine injection, by weight percentage, nimodipine is 0.02%, polyethylene glycol 400 is 17% - 30%, ethanol is 15% - 22%, citric acid is 0.03%, sodium citrate is 0.2%, and water for injection is 54% - 63%.

[0018] In some specific embodiments, the dosage of nimodipine in every 100 mL of the liquid preparation is 0.01 - 0.03 g, preferably 0.02 g.

[0019] In some specific embodiments, the dosage of ethanol in every 100 mL of the liquid preparation is 15 g - 22 g. For example, the dosage of ethanol can be selected from 15 g, 17 g, 19 g, 20 g, 22 g.

[0020] In some specific embodiments, the dosage of polyethylene glycol 400 in every 100 mL of the liquid preparation is 17 g - 30 g. For example, the dosage of polyethylene glycol 400 can be selected from 17 g, 19 g, 22 g, 25 g, 30 g.

[0021] In some specific embodiments, the dosage of citric acid in every 100 mL of the liquid preparation is 0.02 g - 0.04 g, preferably 0.03 g.

[0022] In some specific embodiments, the dosage of sodium citrate in every 100 mL of the liquid preparation is 0.1 - 0.3 g, preferably 0.2 g.

[0023] In the present invention, the content of reducing substances in polyethylene glycol 400 is less than 40 ppm.

[0024] Further, the content of reducing substances in polyethylene glycol 400 is less than 16 ppm.

[0025] Further, the content of reducing substances in polyethylene glycol 400 is less than 10 ppm.

[0026] The present invention also provides a nimodipine injection, which comprises nimodipine, polyethylene glycol 400, ethanol, citric acid, sodium citrate and water for injection. The polyethylene glycol 400 contains reducing substances, and the content of the reducing substances relative to polyethylene glycol 400 does not exceed 40 ppm (specifically, for example, does not exceed 38.5 ppm), preferably does not exceed 16 ppm (specifically, for example, does not exceed 15.5 ppm), and more preferably does not exceed 10 ppm (specifically, for example, does not exceed 8 ppm).

[0027] The applicant surprisingly found that for the nimodipine injection containing the treated polyethylene glycol 400 in the present invention, the product quality was significantly improved, and the total impurity content was much lower than that of the existing products. The applicant also surprisingly found that for the nimodipine injection containing the treated polyethylene glycol 400 in the present invention, the stability was greatly improved. For the nimodipine injection containing the treated polyethylene glycol 400 in the present invention, the increase in impurities during high-temperature storage or long-term storage is less and slower than that of the existing products, and it is more in line with the drug passing standards; even in some preferred embodiments, for the nimodipine injection containing the treated polyethylene glycol 400 in the present invention, it remains stable during high-temperature or long-term storage, and the quality remains unchanged.

[0028] The present invention also provides a preparation method for the above-mentioned nimodipine injection, which comprises the following steps: ① Pretreat polyethylene glycol 400; ② Mix the raw materials; ③ Sterilize and filter.

[0029] The mixing form of mixing the raw materials is not limited. It can be directly mixing all the raw materials together, or mixing and making up the volume after low-oxygen treatment of polyethylene glycol, or mixing some raw materials first and then mixing with the remaining raw materials, and so on.

[0030] Further, the sterilizing and filtering is carried out by filtering with a 0.22 μm filter membrane.

[0031] Further, after sterilizing and filtering, filling, charging a protective gas and sealing are carried out; the protective gas is selected from nitrogen and / or inert gas;

[0032] Further, the residual oxygen in the headspace inside the product after sealing ranges from ≤3.0%.

[0033] Further, after sealing, it is sterilized at 110-130 °C for 10-20 min, preferably sterilized at 121 °C for 15 min.

[0034] The beneficial effects of the present invention are as follows: for the nimodipine injection of the present invention, by pretreating the auxiliary material polyethylene glycol 400 in a specific manner of the present invention, the prepared nimodipine injection has good stability and low impurity content.

[0035] In the present invention, the ethanol may be an aqueous ethanol solution with a volume concentration of 75% to 100% or absolute ethanol, specifically meaning that the ethanol may be an aqueous ethanol solution with an ethanol volume concentration greater than or equal to 75%, or it may be absolute ethanol. In practice, commonly used are ethanol with 95%, 96%, 98% or absolute ethanol, that is, an aqueous ethanol solution with a volume concentration of 95%, 96%, 98% or absolute ethanol. In certain specific embodiments of the present invention, the ethanol is an aqueous ethanol solution with a volume concentration of 96% to 98% or absolute ethanol.

[0036] In the present invention, in certain cases, water for injection can be equivalently replaced by purified water, ultrapure water, etc.

[0037] In the present invention, "an appropriate amount" means more than the prescription amount. Usually, "an appropriate amount" can be the sum of the prescription amount, the test amount, the container residue loss amount or more. Detailed implementation manners

[0038] The technical solutions of the present invention will be described clearly and completely below. Obviously, the described embodiments are some embodiments of the present invention, rather than all embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0039] Example 1

[0040] Referring to the existing prescription situation, the prescription composition shown in Table 1 is adopted:

[0041] Table 1

[0042] Components Nimodipine Polyethylene Glycol 400 Ethanol Citric Acid Sodium Citrate Water for Injection Dosage 0.2g 170g 200g 0.3g 2.0g 622.3g

[0043] The specific preparation method of nimodipine injection is as follows:

[0044] (1) Take an appropriate amount of polyethylene glycol 400 without any treatment;

[0045] (2) Take the polyethylene glycol 400 in step (1) and detect its content of reducing substances, which is 42.3 ppm;

[0046] (3) Add the polyethylene glycol 400 in step (1) to about 95% of the prescription amount of water for injection and stir well to dissolve;

[0047] (4) Add the prescription amounts of anhydrous citric acid and sodium citrate in sequence and stir until dissolved;

[0048] (5) Add the prescription amounts of ethanol and nimodipine and stir until dissolved;

[0049] (6) Add the remaining water for injection, make up the volume, and stir evenly;

[0050] (7) The liquid medicine is filtered through a 0.22 μm PVDF filter membrane;

[0051] (8) The filtered liquid medicine is filled into medium-borosilicate glass infusion bottles, with the headspace oxygen controlled ≤ 3%, and the bottles are stoppered and crimped;

[0052] (9) Sterilize at 121 °C for 15 min to obtain nimodipine injection.

[0053] Samples of the injection are taken for inspection, with the content being 100.1% and the total impurities being 0.85%.

[0054] Example 2

[0055] Prepare nimodipine injection using the prescription in Example 1, and the specific preparation method is as follows:

[0056] (1) Take an appropriate amount of polyethylene glycol 400, place it in a stainless steel container, fill it with nitrogen to control the dissolved oxygen ≤ 1.0 mg / L, heat it at 90 °C ± 5 °C for 1 h, and protect it with nitrogen throughout the process. After heating, take it out and cool it to room temperature;

[0057] (2) Take the polyethylene glycol 400 in step (1) and detect its content of reducing substances, which is 41.8 ppm;

[0058] (3) Add the polyethylene glycol 400 in step (1) to about 95% of the prescription amount of water for injection and stir well to dissolve;

[0059] (4) Add the prescription amounts of anhydrous citric acid and sodium citrate in sequence and stir until dissolved;

[0060] (5) Add the prescription amounts of ethanol and nimodipine and stir until dissolved;

[0061] (6) Add the remaining water for injection, make up the volume, and stir evenly;

[0062] (7) The liquid medicine is filtered through a 0.22 μm PVDF filter membrane;

[0063] (8) The filtered liquid medicine is filled into medium-borosilicate glass infusion bottles, with the headspace oxygen controlled ≤ 3%, and the bottles are stoppered and crimped;

[0064] (9) Sterilize at 121 °C for 15 min to obtain nimodipine injection.

[0065] Samples of the injection are taken for inspection, with the content being 100.8% and the total impurities being 0.86%

[0066] Example 3

[0067] Prepare nimodipine injection using the prescription in Example 1, and the specific preparation method is as follows:

[0068] (1) Take an appropriate amount of polyethylene glycol 400 and place it in a stainless-steel container. Control the dissolved oxygen ≤ 1.0 mg / L by filling with nitrogen. Heat it at 110°C ± 5°C for 1 h and protect it with nitrogen throughout the process. After heating, take it out and cool it to room temperature;

[0069] (2) Take the polyethylene glycol 400 in step (1) and detect its content of reducing substances, which is 38.5 ppm;

[0070] (3) Add the polyethylene glycol 400 in step (1) to about 95% of the prescription amount of injection water and stir well to dissolve;

[0071] (4) Add the prescription amounts of anhydrous citric acid and sodium citrate in sequence and stir until dissolved;

[0072] (5) Add the prescription amounts of ethanol and nimodipine and stir until dissolved;

[0073] (6) Add the remaining injection water, make up the volume, and stir evenly;

[0074] (7) Filter the liquid medicine through a 0.22-μm PVDF filter membrane;

[0075] (8) Subpackage the filtered liquid medicine in a middle-borosilicate glass infusion bottle, control the headspace oxygen ≤ 3%, and stopper and crimp the bottle;

[0076] (9) Sterilize at 121°C × 15 min to obtain nimodipine injection.

[0077] Take a sample of the injection for inspection, the content is 100.6%, and the total impurities are 0.49%.

[0078] Example 4

[0079] Use the prescription in Example 1 to prepare nimodipine injection. The specific preparation method is as follows:

[0080] (1) Take an appropriate amount of polyethylene glycol 400 and place it in a stainless-steel container. Control the dissolved oxygen ≤ 1.0 mg / L by filling with nitrogen. Heat it at 130°C ± 5°C for 1 h and protect it with nitrogen throughout the process. After heating, take it out and cool it to room temperature;

[0081] (2) Take the polyethylene glycol 400 in step (1) and detect its content of reducing substances, which is 7.5 ppm;

[0082] (3) Add the polyethylene glycol in step (1) of the prescription amount to about 95% of the prescription amount of injection water and stir well to dissolve;

[0083] (4) Add the prescription amounts of anhydrous citric acid and sodium citrate in sequence and stir until dissolved;

[0084] (5) Add the prescription amounts of ethanol and nimodipine and stir until dissolved;

[0085] (6) Add the remaining water for injection, make up the volume, and stir evenly.

[0086] (7) Filter the liquid medicine through a 0.22-μm PVDF membrane filter.

[0087] (8) Dispense the filtered liquid medicine into intermediate borosilicate glass infusion bottles, control the headspace oxygen ≤ 3%, and stopper and crimp the caps.

[0088] (9) Sterilize at 121 °C for 15 min to obtain nimodipine injection.

[0089] Samples of the injection were taken for inspection, with a content of 101.0% and a total impurity of 0.11%.

[0090] Example 5

[0091] Prepare nimodipine injection using the prescription in Example 1. The specific preparation method is as follows:

[0092] (1) Take an appropriate amount of polyethylene glycol 400 and place it in a stainless-steel container. Fill with nitrogen to control the dissolved oxygen ≤ 1.0 mg / L, heat at 150 °C ± 5 °C for 1 h, and protect with nitrogen throughout the process. After heating, take it out and cool to room temperature.

[0093] (2) Take the polyethylene glycol 400 in step (1) and detect its content of reducing substances, which is 15.22 ppm.

[0094] (3) Add the polyethylene glycol 400 in step (1) in the prescription amount to about 95% of the prescription amount of water for injection and stir well to dissolve.

[0095] (4) Add the anhydrous citric acid and sodium citrate in the prescription amount in sequence and stir until dissolved.

[0096] (5) Add the ethanol and nimodipine in the prescription amount and stir until dissolved.

[0097] (6) Add the remaining water for injection, make up the volume, and stir evenly.

[0098] (7) Filter the liquid medicine through a 0.22-μm PVDF membrane filter.

[0099] (8) Dispense the filtered liquid medicine into intermediate borosilicate glass infusion bottles, control the headspace oxygen ≤ 3%, and stopper and crimp the caps.

[0100] (9) Sterilize at 121 °C for 15 min to obtain nimodipine injection.

[0101] Samples of the injection were taken for inspection, with a content of 100.7% and a total impurity of 0.37%.

[0102] Example 6

[0103] Referring to the existing prescription situation, the prescription composition shown in Table 2 is adopted:

[0104] Table 2

[0105] Components Nimodipine Polyethylene Glycol 400 Ethanol Citric Acid Sodium Citrate Water for Injection Dosage 0.2g 300g 150g 0.3g 2.0g 547.4g

[0106] The specific preparation method of nimodipine injection is as follows:

[0107] (1) Take an appropriate amount of polyethylene glycol 400, place it in a stainless steel container, heat it at 130°C ± 5°C for 1 h, and protect it with nitrogen throughout the process. After heating, take it out and cool it to room temperature;

[0108] (2) Take the polyethylene glycol 400 in step (1) and detect that the content of reducing substances is 7.8 ppm;

[0109] (3) Add the polyethylene glycol 400 in the prescription amount in step (1) to about 95% of the prescription amount of injection water and stir well to dissolve;

[0110] (4) Add the prescription amounts of anhydrous citric acid and sodium citrate in sequence and stir until dissolved;

[0111] (5) Add the prescription amounts of ethanol and nimodipine and stir until dissolved;

[0112] (6) Add the remaining injection water, make up the volume, and stir evenly;

[0113] (7) Filter the medicinal liquid through a 0.22 μm PVDF filter membrane;

[0114] (8) Subpackage the filtered medicinal liquid in a medium-borosilicate glass infusion bottle, control the headspace oxygen ≤ 3%, and stopper and crimp the cap;

[0115] (9) Sterilize at 121°C × 15 min to obtain nimodipine injection.

[0116] Take a sample of the injection for inspection, the content is 100.9%, and the total impurities are 0.15%.

[0117] Example 7

[0118] Referring to the existing prescription situation, the prescription composition shown in Table 3 is adopted:

[0119] Table 3

[0120] Components Nimodipine Polyethylene Glycol 400 Ethanol Citric Acid Sodium Citrate Water for Injection Dosage 0.2g 190g 220g 0.3g 2.0g 584.0g

[0121] The specific preparation method of nimodipine injection is as follows:

[0122] (1) Take an appropriate amount of polyethylene glycol 400, place it in a stainless steel container, heat it at 130°C ± 5°C for 1 h, and protect it with nitrogen throughout the process. After heating, take it out and cool it to room temperature;

[0123] (2) Take the polyethylene glycol 400 in step (1) and detect the content of reducing substances to be 7.6 ppm;

[0124] (3) Add the polyethylene glycol 400 in the amount of the prescription in step (1) to about 95% of the prescription amount of water for injection and stir well to dissolve;

[0125] (4) Add the anhydrous citric acid and sodium citrate in the amounts of the prescription in sequence and stir until dissolved;

[0126] (5) Add the ethanol and nimodipine in the amounts of the prescription and stir until dissolved;

[0127] (6) Add the remaining water for injection, make up the volume, and stir evenly;

[0128] (7) Filter the liquid medicine through a 0.22 μm PVDF filter membrane;

[0129] (8) Subpackage the filtered liquid medicine in a middle-borosilicate glass infusion bottle, control the headspace oxygen ≤ 3%, stopper and crimp the cap;

[0130] (9) Sterilize at 121 °C for 15 min to obtain nimodipine injection.

[0131] Take a sample of the injection for inspection, the content is 101.0%, and the total impurities are 0.12%.

[0132] According to the results of Examples 2 to 7, it can be seen that when using the polyethylene glycol 400 treated by the method of the present invention to prepare nimodipine injection, the total impurities of the obtained injection are greatly reduced, and the quality of the injection is greatly improved.

[0133] Comparative Example 1

[0134] Use the prescription in Example 1 to prepare nimodipine injection, and the specific preparation method is as follows:

[0135] (1) Take the polyethylene glycol 400 and ethanol in the amounts of the prescription, place them in a stainless steel container, control the dissolved oxygen ≤ 1.0 mg / L by nitrogen filling, set the heating temperature at 130 °C for heating, reflux appears in the system, heat for 1 h, and protect with nitrogen throughout the process. After heating, take it out and cool to room temperature;

[0136] (2) Take the mixed solution in step (1) and detect the content of reducing substances therein, which is 40.1 ppm;

[0137] (3) Add the mixed solution of polyethylene glycol 400 and ethanol in step (1) to water for injection and stir well;

[0138] (4) Add the anhydrous citric acid and sodium citrate in the amounts of the prescription in sequence and stir until dissolved;

[0139] (5) Add the prescribed amount of nimodipine and stir until dissolved;

[0140] (6) Add the remaining water for injection, make up the volume, and stir evenly;

[0141] (7) Filter the liquid medicine through a 0.22 μm PVDF filter membrane;

[0142] (8) Dispense the filtered liquid medicine into medium-borosilicate glass infusion bottles, control the headspace oxygen ≤ 3%, and stopper and crimp the caps;

[0143] (9) Sterilize at 121 °C for 15 min to obtain nimodipine injection.

[0144] Sample and test the injection. The content is 100.4%, and the related substances (total impurities) are 0.58%

[0145] Comparative Example 2

[0146] Prepare nimodipine injection using the prescription in Example 1. The specific preparation method is as follows:

[0147] (1) Take the prescribed amount of polyethylene glycol 400 and nimodipine, stir evenly, control the dissolved oxygen ≤ 1.0 mg / L by nitrogen filling, heat at 130 °C ± 5 °C for 1 h, and protect with nitrogen throughout the process. After heating, cool to room temperature; Sample and test the mixture. The content is 97.4%, and the content of related substances (total impurities) is 3.79%

[0148] (2) Add about 95% of the prescribed amount of water for injection and stir evenly;

[0149] (3) Add the prescribed amount of anhydrous citric acid and sodium citrate in sequence and stir until dissolved;

[0150] (4) Add the prescribed amount of ethanol and stir until evenly mixed;

[0151] (4) Add the remaining water for injection, make up the volume, and stir evenly;

[0152] (7) Filter the liquid medicine through a 0.22 μm PVDF filter membrane;

[0153] (8) Dispense the filtered liquid medicine into medium-borosilicate glass infusion bottles, control the headspace oxygen ≤ 3%, and stopper and crimp the caps;

[0154] (9) Sterilize at 121 °C for 15 min to obtain nimodipine injection.

[0155] Sample and test the injection. The content is 97.2%, and the related substances (total impurities) are 3.82%.

[0156] Stability Test of Example 8

[0157] The samples prepared in the above examples and Comparative Example 1 were respectively placed under the conditions of high temperature of 60°C (Table 4) and accelerated conditions of 40°C and 75% RH (Table 5) for investigation, continuously monitoring the content, pH and related substances.

[0158] Table 4

[0159]

[0160] Table 5

[0161]

[0162] From the above results, it can be seen that the preparation (Example 1) made of polyethylene glycol 400 without pretreatment had a relatively high level of related substances at day 0, and the total impurity content at 60°C for 1 month and 40°C for 3 months had exceeded the limit standard. The preparations made of pretreated polyethylene glycol 400 had lower impurity levels than those in Example 1, and the impurity levels of the samples placed under accelerated and high temperature conditions were also lower than those in Example 1. In particular, for Example 4, the total impurity content at day 0 and under subsequent investigation conditions basically remained unchanged and was maintained at a relatively low level.

[0163] From this, it can be seen that the change level of impurities in the preparation is consistent with the change trend of the content of reducing substances in polyethylene glycol 400. When the content of reducing substances in polyethylene glycol 400 is at a relatively low level, the impurity situation of the prepared samples is better, and the stability of the obtained samples is also better. On the contrary, when the content of reducing substances in polyethylene glycol 400 is at a relatively high level, the impurity situation of the prepared samples is worse. By pretreating polyethylene glycol 400 and controlling the content of its reducing substances (for example, <40 ppm, or preferably <16 ppm, or more preferably <10 ppm), the product quality of nimodipine injection can be significantly improved, meeting its quality requirements, and the stability of nimodipine injection can also be unexpectedly and significantly enhanced.

[0164] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A nimodipine injection, characterized in that, It includes pretreated polyethylene glycol 400; the pretreatment method: heating the temperature to 100°C to 160°C.

2. The nimodipine injection according to claim 1, wherein The temperature is 105°C to 155°C; preferably 125 to 155°C.

3. The Nimodipine Injection according to claim 1, characterized in that, The heating time is 30 min to 120 min; further, the heating time is 60 min.

4. The Nimodipine Injection according to claim 1, wherein, The injection also includes: nimodipine, polyethylene glycol 400, ethanol, citric acid, sodium citrate, and water for injection.

5. A nimodipine injection, characterized in that, It includes nimodipine, polyethylene glycol 400, ethanol, citric acid, sodium citrate, and water for injection, wherein the polyethylene glycol 400 contains reducing substances, and the content of the reducing substances relative to polyethylene glycol 400 does not exceed 40 ppm.

6. The Nimodipine injection according to claim 5, characterized in that, The weight percentages of each component are as follows: nimodipine 0.01% to 0.4%, polyethylene glycol 400 15% to 40%, ethanol 15% to 30%, citric acid 0.01% to 0.06%, sodium citrate 0.15% to 0.5%, and water for injection 30% to 70%.

7. The Nimodipine Injection according to claim 5, wherein, The weight percentages of each component are as follows: nimodipine 0.01% to 0.4%, polyethylene glycol 400 17% to 30%, ethanol 15% to 22%, citric acid 0.02% to 0.05%, sodium citrate 0.18% to 0.3%, and water for injection 45% to 70%.

8. The Nimodipine injection according to claim 1, wherein The content of reducing substances in polyethylene glycol 400 is lower than 40 ppm.

9. The Nimodipine Injection according to claim 1, wherein, The content of reducing substances in polyethylene glycol 400 is lower than 16 ppm, preferably lower than 10 ppm.

10. The preparation method of the nimodipine injection according to any one of claims 1 to 9, characterized in that, It includes the following: ① Pretreat polyethylene glycol 400; ② Mix the raw materials; ③ Sterilize and filter. Further, the sterilization filtration is filtration with a 0.22 μm filter membrane.

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