Metoclopramide hydrochloride injection and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a metoclopramide hydrochloride injection and a preparation method thereof. The metoclopramide hydrochloride injection is prepared from metoclopramide, a hydrochloric acid solution, hydroxypropyl-gamma-cyclodextrin, a cosolvent, sodium chloride, a pH regulator and water for injection, the cosolvent comprises at least one of an alcohol solvent or an amide solvent. Hydroxypropyl-gamma-cyclodextrin has a unique annular structure, a large cavity and good biocompatibility and can form an inclusion compound with metoclopramide hydrochloride molecules, drug molecules are wrapped in the cavity of the inclusion compound, drugs are protected against influences of external environmental factors through the inclusion effect, degradation and deterioration of the drugs are reduced, and the bioavailability of the drugs is improved. The stability and the bioavailability of the injection in the storage process are favorably improved. The cosolvent and the hydroxypropyl-gamma-cyclodextrin can achieve a synergistic effect, so that the solubility and the stability of the medicine are improved, and the problem that the injection is separated out after being placed for a long time is solved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a metoclopramide hydrochloride injection and a preparation method thereof. Background Art

[0002] Metoclopramide hydrochloride injection is a pharmaceutical preparation mainly used to treat symptoms such as nausea, vomiting, belching, indigestion, stomach bloating, excessive gastric acid, etc. caused by various causes. It acts on the human nervous system and digestive system to promote gastrointestinal motility and stop vomiting.

[0003] The metoclopramide hydrochloride injection currently on the market in China is a sterile aqueous solution made by adding an appropriate amount of hydrochloric acid to metoclopramide. It is prepared by the salt-forming process of adding hydrochloric acid solution (see the 2020 edition of the Chinese Pharmacopoeia). The molecular structure of metoclopramide hydrochloride contains functional groups such as amino groups, chlorine atoms, and methoxy groups, which have certain chemical activities. For example, amino groups are easily oxidized. Under the action of oxygen in the air, oxidation reactions may occur, resulting in changes in the structure of the drug (referring to metoclopramide hydrochloride) and the generation of oxidation products, thereby affecting the stability and efficacy of the drug; amide bonds may also undergo hydrolysis reactions under certain conditions, especially in acidic or alkaline environments. The hydrolysis rate may accelerate, causing the drug to decompose into other products, reducing the drug content and affecting the quality and efficacy of the drug. Based on the above reasons, metoclopramide failed to fully form salts and was easy to precipitate during storage, resulting in the appearance of visible foreign matter in metoclopramide hydrochloride injection, which is unqualified, and there are great risks to clinical drug safety. In addition, the pH value of metoclopramide hydrochloride injection currently available in the domestic market ranges from 2.5 to 4.5, which is relatively low and can easily cause discomfort to patients during clinical use. Therefore, it is urgent to develop a metoclopramide hydrochloride injection with stable product quality and less impurities during storage. Summary of the invention

[0004] Aiming at the problem that the existing metoclopramide hydrochloride injection is easy to precipitate after long-term storage, the present invention provides a metoclopramide hydrochloride injection and a preparation method thereof. Hydroxypropyl-γ-cyclodextrin and a cosolvent are added to the metoclopramide hydrochloride injection, and the two can significantly improve the stability of the metoclopramide hydrochloride injection after long-term storage through synergistic effect, and further reduce the content of impurities in the injection after long-term storage.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is: In a first aspect, the present invention provides a metoclopramide hydrochloride injection, comprising the following components: metoclopramide, hydrochloric acid solution, hydroxypropyl-γ-cyclodextrin, a cosolvent, sodium chloride, a pH regulator and water for injection; the cosolvent comprises at least one of an alcohol solvent or an amide solvent.

[0006] Compared with the prior art, the metoclopramide hydrochloride injection (hereinafter referred to as the injection) provided by the present invention has a unique cyclic structure, a relatively large cavity and good biocompatibility, and can form an inclusion complex with metoclopramide hydrochloride (methoclopramide and hydrochloric acid solution form a salt) molecules, wrapping the drug molecules in its cavity, thereby increasing the solubility of the drug in water to a certain extent, and protecting metoclopramide hydrochloride from the influence of external environmental factors (such as light, heat, oxygen, etc.) through inclusion complexation, reducing the degradation and deterioration of the drug, and helping to improve the stability and bioavailability of the injection during storage. Although only adding hydroxypropyl-γ-cyclodextrin can improve the solubility of metoclopramide hydrochloride to a certain extent and reduce the precipitation of metoclopramide hydrochloride in the short term, after long-term storage, metoclopramide hydrochloride will inevitably precipitate, and after testing, its impurity content will also show a significant increase trend. The present invention has found through a large number of experiments that by adding a cosolvent to the injection solution added with hydroxypropyl-γ-cyclodextrin, the problem of poor stability of the injection solution after long-term storage can be significantly improved.

[0007] Further research has found that alcohol solvents or amide solvents can play a synergistic role with hydroxypropyl-γ-cyclodextrin, greatly improving the solubility and stability of metoclopramide hydrochloride, thereby solving the problem of precipitation of injection solution after long-term storage. Alcohol solvents or amide solvents can also be used as a dissolving medium for drugs, so that metoclopramide hydrochloride can be evenly dispersed in water for injection, which is convenient for injection and ensures that the drug can be quickly released and absorbed in the body.

[0008] Preferably, the added amount of metoclopramide is 4.3 mg / mL to 4.6 mg / mL.

[0009] Preferably, the mass concentration of the hydrochloric acid solution is 3% to 6%.

[0010] Preferably, the amount of hydrochloric acid solution added is 9 mg / mL to 18 mg / mL.

[0011] Metoclopramide hydrochloride, formed by the salt formation of metoclopramide and hydrochloric acid solution, is a dopamine receptor antagonist that can act on the gastrointestinal tract and central nervous system to exert pharmacological effects such as antiemetic and promoting gastrointestinal motility. It is the key ingredient in the injection solution to exert its efficacy.

[0012] Preferably, the amount of hydroxypropyl-γ-cyclodextrin added is 11 mg / mL~13 mg / L.

[0013] Preferably, the amount of the co-solvent added is 4.5 mg / mL to 5.5 mg / L.

[0014] Preferably, the amount of sodium chloride added is 7 mg / mL to 8 mg / mL.

[0015] In the present invention, sodium chloride is used as an osmotic pressure regulator, which can make the osmotic pressure of the injection solution close to the osmotic pressure of human plasma within a specific concentration range, reduce discomfort during injection, and avoid damage to blood vessels and cells.

[0016] The invention defines the dosage relationship among metoclopramide, hydrochloric acid solution, hydroxypropyl-γ-cyclodextrin, cosolvent and sodium chloride, can further improve the solubility of metoclopramide hydrochloride, and can also solve the problem of precipitation of metoclopramide hydrochloride injection after long-term storage; the preferred ratio prevents the increase of impurity content in the injection, thereby greatly improving the stability of the injection.

[0017] Preferably, the alcohol solvent includes at least one of ethanol, propylene glycol or polyethylene glycol.

[0018] The preferred alcohol solvent of the present invention has good solubility and volatility, is miscible with water and many organic solvents, has moderate polarity, and forms hydrogen bonds and other molecular interactions with metoclopramide hydrochloride molecules and hydroxypropyl-γ-cyclodextrin, thereby increasing the solubility of the drug and hydroxypropyl-γ-cyclodextrin in water for injection, and at the same time helps to disperse and stabilize the drug in the injection solution.

[0019] Preferably, the amide solvent includes at least one of dimethylformamide (DMF) or dimethylacetamide (DMA).

[0020] The preferred amide solvent of the present invention is a highly polar organic solvent, which has good solubility and solubility-promoting effect, can be miscible with water and various organic solvents, and forms specific interactions with metoclopramide hydrochloride molecules and hydroxypropyl-γ-cyclodextrin to increase the solubility of the drug and hydroxypropyl-γ-cyclodextrin.

[0021] Preferably, the co-solvent comprises an alcohol solvent and an amide solvent in a mass ratio of (3-4):1.

[0022] The preferred cosolvent of the present invention can strengthen its interaction with metoclopramide hydrochloride molecules, encapsulate drug molecules and hydroxypropyl-γ-cyclodextrin, increase the synergistic effect of the cosolvent and hydroxypropyl-γ-cyclodextrin, improve the solubility of the drug in the injection solution, and has a certain protective effect on the drug and hydroxypropyl-γ-cyclodextrin, thereby reducing the degradation of the drug during storage.

[0023] Preferably, the pH adjuster includes at least one of sodium hydroxide, sodium carbonate, sodium acetate, sodium bicarbonate, sodium citrate, phosphate buffer, acetate buffer or citrate buffer.

[0024] Preferably, the pH of the metoclopramide hydrochloride injection is 4-7, more preferably 6-7.

[0025] After metoclopramide hydrochloride is salted, it has a high solubility within a specific pH range, and the degree of drug ionization is not easily changed, so it is not easy to precipitate. In addition, the pH value of human blood is usually between 7.3 and 7.5. The specific pH range of the injection can effectively reduce the stimulation to blood vessels and tissues, ensuring the stability and effectiveness of the drug.

[0026] In a second aspect, the present invention provides a method for preparing the metoclopramide hydrochloride injection, comprising the following steps: S1, under an inert atmosphere, add 75% to 85% of the prescription amount of water for injection, metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride to a preparation tank in sequence and mix, add water for injection to the total amount of preparation, add a pH adjuster, and obtain a metoclopramide hydrochloride solution; S2, filtering the metoclopramide hydrochloride liquid, filling it into an ampoule bottle under an inert atmosphere, and sterilizing it to obtain a metoclopramide hydrochloride injection.

[0027] The present invention provides a preparation method of the metoclopramide hydrochloride injection, by controlling the order of adding metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride and the distribution ratio of water for injection, the solubility of the injection is further improved, and the stability of metoclopramide hydrochloride after long-term storage is excellent, and no precipitation phenomenon occurs. The present invention performs mixed preparation and potting of raw materials under an inert atmosphere, further improves the long-term stability of the injection, ensures that it will not be degraded and deteriorated after long-term storage, controls the growth of impurity content in the injection, and thus effectively improves the quality and efficacy of the injection.

[0028] Preferably, in S1-S2, the inert atmosphere is a nitrogen atmosphere or a carbon dioxide atmosphere.

[0029] Preferably, in S1, the mixing temperature is 20°C to 30°C, the stirring rate is 200rpm to 300rpm, and the mixing time is 15min to 20min.

[0030] Preferably, in S1, the oxygen content of the metoclopramide hydrochloride solution is ≤2ppm.

[0031] Preferably, in S2, the filtration uses a two-stage polyethersulfone filter element.

[0032] Further preferably, in S2, the pore size of the first-stage polyethersulfone filter element in the two-stage polyethersulfone filter element is 0.45 µm, and the pore size of the second-stage polyethersulfone filter element is 0.22 µm.

[0033] The present invention adopts a two-stage polyethersulfone filter element with a specific pore size for sequential filtration, which can not only ensure that the bacteria and endotoxin content of the product are qualified, but also ensure that the particles and visible foreign matter of the product are qualified. In addition, no activated carbon is used in the production process, which reduces the pollution to the production clean area, alleviates the environmental protection pressure, and also reduces the impurities and insoluble particles that may be introduced by the activated carbon, which is conducive to further improving the effectiveness, safety and stability of product quality.

[0034] For example, in S2, the ampoule is a sterilized borosilicate glass ampoule.

[0035] Preferably, in S2, the volume content of oxygen in the ampoule is ≤3%.

[0036] Preferably, in S2, the sterilization temperature is 120°C to 125°C, and the sterilization time is 15 min to 20 min.

[0037] The sterilization conditions provided by the present invention improve the impurity level of the product and also enhance the sterility assurance level of the product.

[0038] The preparation method of the metoclopramide hydrochloride injection provided by the invention improves the storage stability of the metoclopramide hydrochloride injection, does not significantly increase the impurity content in stability and acceleration investigation tests, and does not precipitate when the injection is placed for a long time, thereby improving production efficiency, reducing production costs, facilitating industrial production, and having broad application prospects. DETAILED DESCRIPTION

[0039] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0040] In order to better illustrate the present invention, further examples are given below.

[0041] Example 1 This embodiment provides a metoclopramide hydrochloride injection, and the prescription dosage is as follows: 8.92g of metoclopramide, 27.2g of 4wt% hydrochloric acid solution, 22g of hydroxypropyl-γ-cyclodextrin, 10g of cosolvent (8g of polyethylene glycol, 2g of DMF), 15g of sodium chloride, pH regulator (the amount added is based on pH=6.5) and water for injection (based on a total volume of 2L). The concentration of metoclopramide hydrochloride in the injection is 5.0mg / mL.

[0042] The preparation method of the above-mentioned metoclopramide hydrochloride injection comprises the following steps: S1. Weigh each prescription component according to the designed ratio. In a N2 atmosphere, add 80% of the prescription amount of water for injection, metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride into the preparation tank in sequence. Mix at room temperature and 250rpm for 18min. Add water for injection to 2L, add pH adjuster, and obtain metoclopramide hydrochloride solution with pH=6.5 and oxygen content ≤2ppm.

[0043] S2, filtering the metoclopramide hydrochloride solution through a two-stage polyethersulfone filter element, wherein the pore size of the first-stage polyethersulfone filter element is 0.45µm, and the pore size of the second-stage polyethersulfone filter element is 0.22µm, and filling it into a sterilized borosilicate glass ampoule under a N2 atmosphere, wherein the volume content of oxygen in the ampoule is ≤3%, and sterilizing at 121°C for 17 minutes to obtain metoclopramide hydrochloride injection.

[0044] Example 2 The present embodiment provides a metoclopramide hydrochloride injection, and the prescription dosage is as follows: 8.92 g of metoclopramide, 36.2 g of 3 wt% hydrochloric acid solution, 24 g of hydroxypropyl-γ-cyclodextrin, 9 g of cosolvent (7 g of propylene glycol, 2 g of DMA), 14 g of sodium chloride, a pH adjuster (the amount added is based on pH=6.0) and water for injection (based on a total volume of 2 L).

[0045] The preparation method of the above-mentioned metoclopramide hydrochloride injection comprises the following steps: S1. Weigh each prescription component according to the designed ratio. In a CO2 atmosphere, add 75% of the prescription amount of water for injection, metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride to the preparation tank in sequence. Mix at room temperature and 200rpm for 20min. Add water for injection to 2L, add pH adjuster, and obtain metoclopramide hydrochloride solution with pH=6.0 and oxygen content ≤2ppm. S2, filtering the metoclopramide hydrochloride solution through a two-stage polyethersulfone filter element, wherein the pore size of the first-stage polyethersulfone filter element is 0.45µm, and the pore size of the second-stage polyethersulfone filter element is 0.22µm, and filling it into a sterilized borosilicate glass ampoule under a CO2 atmosphere, wherein the volume content of oxygen in the ampoule is ≤3%, and sterilizing at 120°C for 20 minutes to obtain metoclopramide hydrochloride injection.

[0046] Example 3 This embodiment provides a metoclopramide hydrochloride injection, and the prescription dosage is as follows: 8.92 g of metoclopramide, 18.1 g of 6 wt% hydrochloric acid solution, 26 g of hydroxypropyl-γ-cyclodextrin, 11 g of cosolvent (8.3 g of ethanol, 2.7 g of DMF), 16 g of sodium chloride, a pH adjuster (the amount added is based on pH = 6.8) and water for injection (based on a total volume of 2 L).

[0047] The preparation method of the above-mentioned metoclopramide hydrochloride injection comprises the following steps: S1. Weigh each prescription component according to the designed ratio. In a N2 atmosphere, add 85% of the prescription amount of water for injection, metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride into the preparation tank in sequence. Mix at room temperature and 300 rpm for 15 minutes. Add water for injection to 2L and add pH adjuster to obtain metoclopramide hydrochloride solution with pH = 6.8 and oxygen content ≤ 2ppm.

[0048] S2, filtering the metoclopramide hydrochloride solution through a two-stage polyethersulfone filter element, wherein the pore size of the first-stage polyethersulfone filter element is 0.45µm, and the pore size of the second-stage polyethersulfone filter element is 0.22µm, and filling it into a sterilized borosilicate glass ampoule under a N2 atmosphere, wherein the volume content of oxygen in the ampoule is ≤3%, and sterilizing at 125°C for 15 minutes to obtain metoclopramide hydrochloride injection.

[0049] Example 4 This embodiment provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that the co-solvent is replaced with 10 g of propylene glycol. The remaining components and contents are the same as those in Example 1 and will not be described in detail.

[0050] The preparation method of the above metoclopramide hydrochloride injection is the same as that in Example 1 and will not be repeated herein.

[0051] Example 5 This embodiment provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that the cosolvent is replaced with 10 g of DMF. The remaining components and contents are the same as those in Example 1 and will not be described in detail.

[0052] The preparation method of the above metoclopramide hydrochloride injection is the same as that in Example 1 and will not be repeated herein.

[0053] Example 6 This embodiment provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that the cosolvent is replaced with 5 g of polyethylene glycol and 5 g of DMF. The remaining components and contents are the same as those in Example 1 and will not be described in detail.

[0054] The preparation method of the above metoclopramide hydrochloride injection is the same as that in Example 1 and will not be repeated herein.

[0055] Example 7 This embodiment provides a metoclopramide hydrochloride injection, which is similar to Embodiment 1, except that the amount of the pH adjuster added is based on pH = 3. The remaining components and contents are the same as those in Embodiment 1 and will not be described in detail.

[0056] The preparation method of the above metoclopramide hydrochloride injection is the same as that in Example 1 and will not be repeated herein.

[0057] Comparative Example 1 This comparative example provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that the co-solvent is replaced with hydroxypropyl-γ-cyclodextrin of the same mass. The remaining components and contents are the same as those in Example 1 and will not be described in detail.

[0058] The preparation method of the above metoclopramide hydrochloride injection is similar to that of Example 1, except that the co-solvent is omitted and will not be described in detail.

[0059] Comparative Example 2 This comparative example provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that the co-solvent is replaced with water for injection of equal quality. The remaining components and contents are the same as those in Example 1 and will not be described in detail.

[0060] The preparation method of the above metoclopramide hydrochloride injection is similar to that of Example 1, except that the co-solvent is omitted and will not be described in detail.

[0061] Comparative Example 3 This comparative example provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with a cosolvent (in the cosolvent, polyethylene glycol is 25.6 g and DMF is 6.4 g). The remaining components and contents are the same as those in Example 1 and will not be described in detail.

[0062] The preparation method of the above metoclopramide hydrochloride injection is similar to that of Example 1, except that hydroxypropyl-γ-cyclodextrin is omitted and will not be described in detail.

[0063] Comparative Example 4 This comparative example provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with water for injection of the same mass. The remaining components and contents are the same as those in Example 1 and will not be described in detail.

[0064] The preparation method of the above metoclopramide hydrochloride injection is similar to that of Example 1, except that hydroxypropyl-γ-cyclodextrin is omitted and will not be described in detail.

[0065] Comparative Example 5 This comparative example provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with hydroxypropyl-β-cyclodextrin of the same mass. The remaining components and contents are the same as those in Example 1 and are not described in detail.

[0066] The preparation method of the above metoclopramide hydrochloride injection is similar to that of Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced by hydroxypropyl-β-cyclodextrin, which will not be described in detail.

[0067] Comparative Example 6 This comparative example provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with hydroxypropyl-α-cyclodextrin of the same mass. The remaining components and contents are the same as those in Example 1 and are not described in detail.

[0068] The preparation method of the above metoclopramide hydrochloride injection is similar to that of Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced by hydroxypropyl-α-cyclodextrin, which will not be described in detail.

[0069] Comparative Example 7 This comparative example provides a metoclopramide hydrochloride injection, which is similar to Example 1, except that the co-solvent is replaced with N-methylpyrrolidone (NMP) of the same mass. The remaining components and contents are the same as those in Example 1 and will not be described in detail.

[0070] The preparation method of the above metoclopramide hydrochloride injection is similar to that of Example 1, except that the co-solvent is replaced by NMP, which will not be described in detail.

[0071] Comparative Example 8 This comparative example provides a preparation method of metoclopramide hydrochloride injection, which is similar to Example 1, except that: in S1-S2, the operation is performed under air atmosphere. The remaining steps are the same as those in Example 1 and will not be repeated.

[0072] The prescription of the injection is exactly the same as that of Example 1 and will not be repeated herein.

[0073] Comparative Example 9 This comparative example provides a method for preparing metoclopramide hydrochloride injection, which is similar to Example 1, except that: in S1, the order of adding hydroxypropyl-γ-cyclodextrin and the cosolvent is replaced. The remaining steps are the same as those in Example 1 and will not be repeated.

[0074] The prescription of the injection is exactly the same as that of Example 1 and will not be repeated herein.

[0075] Verification test At 40°C±2°C and RH=75%±5%, the metoclopramide hydrochloride injections provided in Examples 1-7 and Comparative Examples 1-9 were subjected to an accelerated test. The test results are shown in Table 1.

[0076] Table 1 Accelerated test results of injection

[0077] The metoclopramide hydrochloride injections provided in Examples 1 to 7 and Comparative Examples 1 to 9 were subjected to stability tests at 30°C ± 2°C and RH = 65% ± 5%. The test results are shown in Table 2.

[0078] Table 2 Test results of stability test of injection

[0079] The single impurities in Table 1 and Table 2 include impurities I to VII and unknown impurities. The single impurity information is as follows: Impurity I is 4-amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide, with a molecular formula of C 12 H 18 ClN3O2; Impurity II is 4-acetylamino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide, with the molecular formula C 16 H 24 ClN3O3; Impurity III is 4-acetylamino-5-chloro-2-methoxy-benzoic acid methyl ester, the molecular formula is C 11 H 12 ClNO4; Impurity IV is 4-amino-5-chloro-2-methoxybenzoic acid, with the molecular formula C8H8ClNO3; Impurity V is 4-acetylamino-2-methoxybenzoic acid methyl ester, with the molecular formula C 11 H 13 NO4; Impurity VI is N, N-diethylethylenediamine, with the molecular formula C 16 H 16 N2; Impurity VII is 4-amino-5-chloro-N-(2-(diethylamino)ethyl)-2-hydroxybenzamide, with the molecular formula C 13 H 20 ClN3O2.

[0080] It can be seen from the above test data that, compared with Comparative Examples 1 to 9, the metoclopramide hydrochloride injection prepared in Examples 1 to 7 of the present invention has lower impurity content and higher stability. The increase in impurity content during the accelerated 3-month and 6-month tests is significantly lower than that in Comparative Examples 1 to 9, and the injection has no precipitation after accelerated placement for 6 months; when doing a long-term stability test, the metoclopramide hydrochloride injection provided by the embodiment of the present invention still has no precipitation after long-term placement for 24 months, and the impurity content is significantly lower than the metoclopramide hydrochloride injection provided in Comparative Examples 1 to 9; this proves that the metoclopramide hydrochloride injection prepared in the embodiment of the present invention has better stability and safety, thereby being more conducive to improving the safety of clinical application.

[0081] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A metoclopramide hydrochloride injection, characterized in that, The invention comprises the following components: metoclopramide, hydrochloric acid solution, hydroxypropyl-γ-cyclodextrin, cosolvent, sodium chloride, pH regulator and water for injection; The auxiliary solvent includes at least one of an alcohol solvent or an amide solvent.

2. The metoclopramide hydrochloride injection according to claim 1, characterized in that: The amount of metoclopramide added is 4.3 mg / mL to 4.6 mg / mL; The mass concentration of the hydrochloric acid solution is 3% to 6%, and the amount of the hydrochloric acid solution added is 9 mg / mL to 18 mg / mL; The amount of hydroxypropyl-γ-cyclodextrin added is 11 mg / mL~13 mg / L; The amount of the cosolvent added is 4.5 mg / mL to 5.5 mg / L; The amount of sodium chloride added is 7 mg / mL to 8 mg / mL.

3. The metoclopramide hydrochloride injection according to claim 1, characterized in that: The alcohol solvent includes at least one of ethanol, propylene glycol or polyethylene glycol; The amide solvent includes at least one of dimethylformamide and dimethylacetamide.

4. The metoclopramide hydrochloride injection according to any one of claims 1 to 3, characterized in that The co-solvent comprises an alcohol solvent and an amide solvent in a mass ratio of (3-4):

1.

5. The metoclopramide hydrochloride injection according to claim 1 or 2, characterized in that: The pH of the metoclopramide hydrochloride injection is 4-7.

6. A method for preparing the metoclopramide hydrochloride injection according to any one of claims 1 to 5, characterized in that: The steps include: S1, under an inert atmosphere, add 75% to 85% of the prescription amount of water for injection, metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride to a preparation tank in sequence and mix, add water for injection to the total amount of preparation, add a pH adjuster, and obtain a metoclopramide hydrochloride solution; S2, filtering the metoclopramide hydrochloride liquid, filling it into an ampoule bottle under an inert atmosphere, and sterilizing it to obtain a metoclopramide hydrochloride injection.

7. The method for preparing metoclopramide hydrochloride injection according to claim 6, characterized in that: In S1, the oxygen content of the metoclopramide hydrochloride solution is ≤2ppm; In S2, the volume content of oxygen in the ampoule is ≤3%.

8. The method for preparing metoclopramide hydrochloride injection according to claim 6, characterized in that: In S1~S2, the inert atmosphere is a nitrogen atmosphere or a carbon dioxide atmosphere.

9. The method for preparing metoclopramide hydrochloride injection according to claim 6, characterized in that: In S2, the filtration uses a two-stage polyethersulfone filter element.

10. The method for preparing metoclopramide hydrochloride injection according to claim 6, characterized in that: In S2, the sterilization temperature is 120°C to 125°C, and the sterilization time is 15min to 20min.

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