A meclizine hydrochloride injection and a method of preparing the same

Abstract

The application relates to the technical field of pharmaceutical preparations, and particularly discloses a methoclopramide hydrochloride injection and a preparation method thereof. The methoclopramide hydrochloride injection comprises methoclopramide, a hydrochloric acid solution, hydroxypropyl-gamma-cyclodextrin, a cosolvent, sodium chloride, a pH regulator and water for injection; and the cosolvent comprises at least one of an alcohol solvent or an amide solvent. The hydroxypropyl-gamma-cyclodextrin has a unique cyclic structure, a large cavity and good biocompatibility, can form an inclusion compound with the methoclopramide hydrochloride molecules, wraps the drug molecules in the cavity, protects the drug from the influence of external environmental factors through the inclusion effect, reduces the degradation and deterioration of the drug, and helps to improve the stability and bioavailability of the injection during storage. The cosolvent can play a synergistic effect with the hydroxypropyl-gamma-cyclodextrin, improve the solubility and stability of the drug, and solve the problem of precipitation of the injection after long-term storage.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a methoclopramide hydrochloride injection and a preparation method thereof. BACKGROUND

[0002] The methoclopramide hydrochloride injection is a pharmaceutical preparation, which is mainly used for treating symptoms such as nausea, vomiting, belching, indigestion, stomach fullness, excessive stomach acid and the like caused by various causes, and plays a role in promoting gastrointestinal peristalsis and antiemesis by acting on the nervous system and the digestive system of the human body.

[0003] At present, the methoclopramide hydrochloride injection on the market in China is a sterile aqueous solution prepared by adding methoclopramide and hydrochloric acid, which is prepared by using a hydrochloric acid solution salting process (see Chinese Pharmacopoeia 2020 edition). The molecular structure of methoclopramide hydrochloride contains functional groups such as amino, chlorine atom and methoxy group. These groups have certain chemical activity. For example, the amino group is easy to be oxidized, and may be oxidized under the action of oxygen in the air, resulting in changes in the structure of the drug (referring to methoclopramide hydrochloride), generating oxidation products, thereby affecting the stability and efficacy of the drug; the amide bond may also hydrolyze under certain conditions, especially in an acidic or alkaline environment, the hydrolysis rate may be accelerated, 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, methoclopramide is not fully salified, and is easy to precipitate during storage, resulting in unqualified methoclopramide hydrochloride injection with visible foreign matter, which has a large hidden danger in clinical drug use. In addition, the pH value of the methoclopramide hydrochloride injection on the market in China is 2.5-4.5, which is relatively low, and is easy to cause discomfort to patients during clinical use. Therefore, there is an urgent need to develop a methoclopramide hydrochloride injection with stable product quality and less impurity content during storage. SUMMARY

[0004] In view of the problem that the existing methoclopramide hydrochloride injection is easy to precipitate during long-term storage, the present application provides a methoclopramide hydrochloride injection and a preparation method thereof. By adding hydroxypropyl-gamma-cyclodextrin and a cosolvent to the methoclopramide hydrochloride injection, the two can significantly improve the stability of the methoclopramide hydrochloride injection after long-term storage through synergistic effect, and further reduce the content of impurities in the injection after long-term storage.

[0005] To solve the above technical problems, the technical scheme provided by the present application is as follows:

[0006] In a first aspect, the present application provides a methoclopramide hydrochloride injection, which comprises the following components: methoclopramide, hydrochloric acid solution, hydroxypropyl-gamma-cyclodextrin, cosolvent, sodium chloride, pH adjuster and water for injection; the cosolvent comprises at least one of an alcohol solvent or an amide solvent.

[0007] Compared with the prior art, the methoclopramide hydrochloride injection provided by the application has a unique cyclic structure, a relatively large cavity and good biocompatibility, and can form an inclusion compound with methoclopramide hydrochloride (methoclopramide and hydrochloric acid solution form a salt), so as to wrap the drug molecules in the cavity, thereby increasing the solubility of the drug in water to a certain extent, protecting the methoclopramide hydrochloride from the influence of external environmental factors (such as light, heat, oxygen, etc.) through the inclusion effect, reducing the degradation and deterioration of the drug, and helping to improve the stability and bioavailability of the injection during storage. Although the addition of hydroxypropyl-γ-cyclodextrin can improve the solubility of methoclopramide hydrochloride to a certain extent and reduce the precipitation of methoclopramide hydrochloride in the short term, methoclopramide hydrochloride will inevitably precipitate after long-term storage, and the impurity content will also increase significantly. Through a large number of experiments, it is found that the addition of a cosolvent to the injection containing hydroxypropyl-γ-cyclodextrin can significantly improve the poor stability of the injection after long-term storage.

[0008] It is found through further research that the alcohol solvent or amide solvent can have a synergistic effect with hydroxypropyl-γ-cyclodextrin, greatly improving the solubility and stability of methoclopramide hydrochloride, thereby solving the problem of precipitation of the injection after long-term storage. The alcohol solvent or amide solvent can also be used as a drug dissolving medium, so that methoclopramide hydrochloride can be uniformly dispersed in water for injection, facilitating injection use, and ensuring rapid release and absorption of the drug in the body.

[0009] Preferably, the methoclopramide is added in an amount of 4.3 mg / mL to 4.6 mg / mL.

[0010] Preferably, the hydrochloric acid solution has a mass concentration of 3% to 6%.

[0011] Preferably, the hydrochloric acid solution is added in an amount of 9 mg / mL to 18 mg / mL.

[0012] Methoclopramide hydrochloride formed by methoclopramide and a hydrochloric acid solution is a dopamine receptor antagonist, which can act on the gastrointestinal tract and the central nervous system, and has pharmacological effects such as antiemesis and promotion of gastrointestinal peristalsis, and is a key component for the injection to exert efficacy.

[0013] Preferably, the hydroxypropyl-γ-cyclodextrin is added in an amount of 11 mg / mL to 13 mg / L.

[0014] Preferably, the cosolvent is added in an amount of 4.5 mg / mL to 5.5 mg / L.

[0015] Preferably, the sodium chloride is added in an amount of 7 mg / mL to 8 mg / mL.

[0016] The sodium chloride in the present application is used as an osmotic pressure regulator, and can make the osmotic pressure of the injection solution similar to that of human plasma in a specific concentration range, thereby reducing the discomfort during injection and avoiding damage to blood vessels and cells.

[0017] The present application defines the amount relationship among metoclopramide, hydrochloric acid solution, hydroxypropyl-γ-cyclodextrin, a co-solvent and sodium chloride, which can further improve the solubility of metoclopramide hydrochloride, and also solve the problem of precipitation of metoclopramide hydrochloride injection during long-term storage; and the preferred ratio prevents the increase of impurities in the injection solution, thereby greatly improving the stability of the injection solution.

[0018] Preferably, the alcohol solvent includes at least one of ethanol, propylene glycol or polyethylene glycol.

[0019] The preferred alcohol solvent in the present application has good solubility and volatility, can be miscible with water and many organic solvents, has moderate polarity, and can form hydrogen bonds and other intermolecular interactions with the molecules of metoclopramide hydrochloride and hydroxypropyl-γ-cyclodextrin, thereby increasing the solubility of the drug and hydroxypropyl-γ-cyclodextrin in water for injection, and also helping the dispersion and stability of the drug in the injection solution.

[0020] Preferably, the amide solvent includes at least one of dimethylformamide (DMF) or dimethylacetamide (DMA).

[0021] The preferred amide solvent in the present application is a strong polar organic solvent, has good solubility and co-solvent effect, can be miscible with water and many organic solvents, and can form specific interactions with the molecules of metoclopramide hydrochloride and hydroxypropyl-γ-cyclodextrin, thereby increasing the solubility of the drug and hydroxypropyl-γ-cyclodextrin.

[0022] Preferably, the co-solvent includes alcohol solvent and amide solvent in a mass ratio of (3-4):1.

[0023] The preferred co-solvent in the present application can strengthen its interaction with the molecules of metoclopramide hydrochloride, wrap the drug molecules and hydroxypropyl-γ-cyclodextrin, increase the synergistic effect of the co-solvent and hydroxypropyl-γ-cyclodextrin, improve the solubility of the drug in the injection solution, and also has a certain protective effect on the drug and hydroxypropyl-γ-cyclodextrin, thereby reducing the degradation of the drug during storage.

[0024] Preferably, the pH regulator includes at least one of sodium hydroxide, sodium carbonate, sodium acetate, sodium bicarbonate, sodium citrate, phosphate buffer, acetate buffer or citrate buffer.

[0025] Preferably, the methoclopramide hydrochloride injection solution has a pH of 4 to 7, and more preferably 6 to 7.

[0026] After methoclopramide hydrochloride is formed into a salt, it has a high solubility in a specific pH range, and the degree of ionization of the drug 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, and the specific pH range of the injection solution can effectively reduce the irritation to blood vessels and tissues, ensuring the stability and effectiveness of the drug.

[0027] In a second aspect, the application provides a preparation method of the methoclopramide hydrochloride injection solution, comprising the following steps:

[0028] S1, under an inert atmosphere, sequentially adding the prescription amount of 75% to 85% of water for injection, methoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride into a preparation tank for mixing, adding water for injection to the total preparation amount, adding a pH adjuster, and obtaining a methoclopramide hydrochloride liquid;

[0029] S2, filtering the methoclopramide hydrochloride liquid, and filling and sealing it into an ampoule under an inert atmosphere, and sterilizing to obtain a methoclopramide hydrochloride injection solution.

[0030] The preparation method of the methoclopramide hydrochloride injection solution provided by the application further improves the solubility of the injection solution by controlling the addition sequence of methoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride, and the distribution ratio of water for injection. After long-term storage, the stability of methoclopramide hydrochloride is excellent and no precipitation occurs. The mixing and filling of the raw materials are carried out under an inert atmosphere, which further improves the long-term stability of the injection solution, ensures that it will not degrade and deteriorate after long-term storage, controls the increase of impurities in the injection solution, and thus effectively improves the quality and efficacy of the injection solution.

[0031] Preferably, in S1-S2, the inert atmosphere is a nitrogen atmosphere or a carbon dioxide atmosphere.

[0032] Preferably, in S1, the mixing temperature is 20°C to 30°C, the stirring rate is 200 rpm to 300 rpm, and the mixing time is 15 min to 20 min.

[0033] Preferably, in S1, the oxygen content of the methoclopramide hydrochloride liquid is ≤2 ppm.

[0034] Preferably, in S2, the filtering uses a two-stage polyether sulfone filter core.

[0035] Further preferably, in S2, the pore size of the first-stage polyether sulfone filter core in the two-stage polyether sulfone filter core is 0.45 µm, and the pore size of the second-stage polyether sulfone filter core is 0.22 µm.

[0036] The application adopts the secondary polyether sulfone filter core with specific pore size to filter in sequence, which can not only ensure the qualified bacterial and endotoxin content of the product, but also ensure the qualified particulate and visible foreign matter of the product, and the activated carbon is not used in the production process, thereby reducing the pollution to the clean production area, reducing the environmental protection pressure, reducing the impurities and insoluble particles possibly introduced by the activated carbon, and being beneficial to further improve the effectiveness, safety and stability of the product quality.

[0037] For example, in S2, the ampoule is a sterilized borosilicate glass ampoule.

[0038] Preferably, in S2, the volume content of oxygen in the ampoule is ≤3%.

[0039] Preferably, in S2, the sterilization temperature is 120-125 DEG C, and the sterilization time is 15-20 min.

[0040] The sterilization condition provided by the application improves the impurity level of the product and also improves the sterile guarantee level of the product.

[0041] The preparation method of the metoclopramide hydrochloride injection provided by the application improves the storage stability of the metoclopramide hydrochloride injection, the increase of impurity content is not obvious in the stability and acceleration investigation test, and the injection does not precipitate after long-term storage, thereby improving the production efficiency, reducing the production cost, facilitating the industrialized production, and having a wide application prospect. DETAILED DESCRIPTION

[0042] In order to make the purpose, technical scheme and advantages of the application more clear and explicit, the application is further described in detail below with examples. It should be understood that the specific examples described herein are only used to explain the application and not to limit the application.

[0043] In order to better illustrate the application, the following examples are further illustrated.

[0044] Example 1

[0045] The example provides a metoclopramide hydrochloride injection, and the prescription amount is as follows: metoclopramide 8.92g, 4wt% hydrochloric acid solution 27.2g, hydroxypropyl-gamma-cyclodextrin 22g, cosolvent 10g (polyethylene glycol 8g, DMF 2g), sodium chloride 15g, pH adjuster (the amount is added according to pH=6.5) and injection water (the total volume is 2L). The concentration of metoclopramide hydrochloride in the injection is 5.0mg / mL.

[0046] The preparation method of the above metoclopramide hydrochloride injection includes the following steps:

[0047] S1, according to the design ratio, weigh each prescription component, under N2 atmosphere, add the prescription amount of 80% water for injection, metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride into the preparation tank in turn, mix at room temperature and 250 rpm for 18 min, add water for injection to 2 L, add pH regulator, and obtain metoclopramide hydrochloride solution with pH=6.5 and oxygen content≤2 ppm.

[0048] S2, filter the metoclopramide hydrochloride solution through two-stage polyether sulfone filter elements, wherein the pore size of the first-stage polyether sulfone filter element is 0.45 µm, and the pore size of the second-stage polyether sulfone filter element is 0.22 µm, fill and seal into sterilized borosilicate glass ampoules under N2 atmosphere, the volume content of oxygen in the ampoule is≤3%, sterilize at 121 ℃ for 17 min, and obtain metoclopramide hydrochloride injection.

[0049] Example 2

[0050] The present embodiment provides a metoclopramide hydrochloride injection, and the prescription amount is as follows: metoclopramide 8.92 g, 3 wt% hydrochloric acid solution 36.2 g, hydroxypropyl-γ-cyclodextrin 24 g, cosolvent 9 g (propylene glycol 7 g, DMA 2 g), sodium chloride 14 g, pH regulator (added amount is based on pH=6.0) and water for injection (based on the total volume of 2 L).

[0051] The preparation method of the above metoclopramide hydrochloride injection includes the following steps:

[0052] S1, according to the design ratio, weigh each prescription component, under CO2 atmosphere, add the prescription amount of 75% water for injection, metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride into the preparation tank in turn, mix at room temperature and 200 rpm for 20 min, add water for injection to 2 L, add pH regulator, and obtain metoclopramide hydrochloride solution with pH=6.0 and oxygen content≤2 ppm.

[0053] S2, filter the metoclopramide hydrochloride solution through two-stage polyether sulfone filter elements, wherein the pore size of the first-stage polyether sulfone filter element is 0.45 µm, and the pore size of the second-stage polyether sulfone filter element is 0.22 µm, fill and seal into sterilized borosilicate glass ampoules under CO2 atmosphere, the volume content of oxygen in the ampoule is≤3%, sterilize at 120 ℃ for 20 min, and obtain metoclopramide hydrochloride injection.

[0054] Example 3

[0055] The embodiment provides a meclizine hydrochloride injection, and the prescription amount is as follows: meclizine 8.92g, 6wt% hydrochloric acid solution 18.1g, hydroxypropyl-gamma-cyclodextrin 26g, cosolvent 11g (ethanol 8.3g, DMF 2.7g), sodium chloride 16g, pH regulator (the addition amount is based on pH=6.8) and injection water (based on the total volume of 2L).

[0056] The preparation method of the meclizine hydrochloride injection includes the following steps:

[0057] S1, according to the designed proportion, each prescription component is weighed, 85% injection water, meclizine, hydroxypropyl-gamma-cyclodextrin, hydrochloric acid solution, cosolvent and sodium chloride are sequentially added into a preparation tank under the atmosphere of N2, and mixed at room temperature and 300rpm for 15min, injection water is added to 2L, a pH regulator is added, and the meclizine hydrochloride liquid with pH=6.8 and oxygen content≤2ppm is obtained.

[0058] S2, the meclizine hydrochloride liquid is filtered through two-stage polyether sulfone filter cores, the pore size of the first-stage polyether sulfone filter core is 0.45µm, the pore size of the second-stage polyether sulfone filter core is 0.22µm, the meclizine hydrochloride liquid is filled and sealed into a sterilized borosilicate glass ampoule under the atmosphere of N2, the volume content of oxygen in the ampoule is≤3%, and the meclizine hydrochloride injection is obtained after sterilization at 125℃ for 15min.

[0059] Embodiment 4

[0060] The embodiment provides a meclizine hydrochloride injection, which is similar to the embodiment 1, and the difference is that the cosolvent is replaced by 10g propylene glycol. The rest of the components and the content are the same as those in the embodiment 1, and details are not repeated.

[0061] The preparation method of the meclizine hydrochloride injection is the same as that in the embodiment 1, and details are not repeated.

[0062] Embodiment 5

[0063] The embodiment provides a meclizine hydrochloride injection, which is similar to the embodiment 1, and the difference is that the cosolvent is replaced by 10g DMF. The rest of the components and the content are the same as those in the embodiment 1, and details are not repeated.

[0064] The preparation method of the meclizine hydrochloride injection is the same as that in the embodiment 1, and details are not repeated.

[0065] Embodiment 6

[0066] The embodiment provides a meclizine hydrochloride injection, which is similar to the embodiment 1, and the difference is that the cosolvent is replaced by 5g polyethylene glycol and 5g DMF. The rest of the components and the content are the same as those in the embodiment 1, and details are not repeated.

[0067] The preparation method of the above-mentioned metoclopramide hydrochloride injection is the same as that in Example 1, and will not be repeated here.

[0068] Example 7

[0069] This embodiment provides a metoclopramide hydrochloride injection solution, similar to Example 1, except that the amount of pH adjuster added is based on pH=3. The remaining components and contents are the same as in Example 1 and will not be described again.

[0070] The preparation method of the above-mentioned metoclopramide hydrochloride injection is the same as that in Example 1, and will not be repeated here.

[0071] Comparative Example 1

[0072] This comparative example provides a metoclopramide hydrochloride injection solution, similar to Example 1, except that the cosolvent is replaced with an equal mass of hydroxypropyl-γ-cyclodextrin. The remaining components and contents are the same as in Example 1 and will not be repeated.

[0073] The preparation method of the above-mentioned metoclopramide hydrochloride injection is similar to that of Example 1, except that the co-solvent is omitted, which will not be described again.

[0074] Comparative Example 2

[0075] This comparative example provides a metoclopramide hydrochloride injection solution, similar to Example 1, except that the cosolvent is replaced with an equal mass of water for injection. The remaining components and contents are the same as in Example 1 and will not be described again.

[0076] The preparation method of the above-mentioned metoclopramide hydrochloride injection is similar to that of Example 1, except that the co-solvent is omitted, which will not be described again.

[0077] Comparative Example 3

[0078] This comparative example provides a metoclopramide hydrochloride injection solution, similar to Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with a cosolvent (the cosolvent contains 25.6g of polyethylene glycol and 6.4g of DMF). The remaining components and contents are the same as in Example 1 and will not be repeated.

[0079] The preparation method of the above-mentioned metoclopramide hydrochloride injection is similar to that of Example 1, except that hydroxypropyl-γ-cyclodextrin is omitted, which will not be described again.

[0080] Comparative Example 4

[0081] This comparative example provides a metoclopramide hydrochloride injection solution, similar to Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with an equal mass of water for injection. The remaining components and contents are the same as in Example 1 and will not be repeated.

[0082] The preparation method of the above-mentioned metoclopramide hydrochloride injection is similar to that of Example 1, except that hydroxypropyl-γ-cyclodextrin is omitted, which will not be described again.

[0083] Comparative Example 5

[0084] This comparative example provides a metoclopramide hydrochloride injection, similar to Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with an equal mass of hydroxypropyl-β-cyclodextrin. The remaining components and contents are the same as in Example 1 and will not be repeated.

[0085] The preparation method of the above-mentioned metoclopramide hydrochloride injection is similar to that of Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with hydroxypropyl-β-cyclodextrin, which will not be described in detail here.

[0086] Comparative Example 6

[0087] This comparative example provides a metoclopramide hydrochloride injection, similar to Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with an equal mass of hydroxypropyl-α-cyclodextrin. The remaining components and contents are the same as in Example 1 and will not be repeated.

[0088] The preparation method of the above-mentioned metoclopramide hydrochloride injection is similar to that of Example 1, except that hydroxypropyl-γ-cyclodextrin is replaced with hydroxypropyl-α-cyclodextrin, which will not be described in detail here.

[0089] Comparative Example 7

[0090] This comparative example provides a metoclopramide hydrochloride injection solution, similar to Example 1, except that the cosolvent is replaced with an equal mass of N-methylpyrrolidone (NMP). The remaining components and contents are the same as in Example 1 and will not be described again.

[0091] The preparation method of the above-mentioned metoclopramide hydrochloride injection is similar to that of Example 1, except that the cosolvent is replaced with NMP, which will not be described again.

[0092] Comparative Example 8

[0093] This comparative example provides a method for preparing metoclopramide hydrochloride injection, similar to Example 1, except that in steps S1-S2, the operation is carried out under an air atmosphere. The remaining steps are the same as in Example 1 and will not be repeated.

[0094] The formulation of the injection is exactly the same as that in Example 1, and will not be repeated here.

[0095] Comparative Example 9

[0096] This comparative example provides a method for preparing metoclopramide hydrochloride injection, similar to Example 1, except that in S1, the order of adding hydroxypropyl-γ-cyclodextrin and the solubilizer is changed. The remaining steps are the same as in Example 1 and will not be repeated.

[0097] The formulation of the injection is exactly the same as that in Example 1, and will not be repeated here.

[0098] Verification test

[0099] Accelerated tests were conducted on the metoclopramide hydrochloride injection solutions provided in Examples 1-7 and Comparative Examples 1-9 at 40℃±2℃ and RH=75%±5%. The test results are shown in Table 1.

[0100] Table 1. Accelerated test results of the injection solution

[0101]

[0102] Stability tests were conducted on the metoclopramide hydrochloride injection solutions provided in Examples 1-7 and Comparative Examples 1-9 at 30℃±2℃ and RH=65%±5%. The test results are shown in Table 2.

[0103] Table 2. Results of stability test of the injection solution

[0104]

[0105] The single impurities listed in Tables 1 and 2 include impurities I through VII and an unknown impurity. Information on single impurities is as follows: Impurity I is 4-amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide, with the molecular formula C1. 12 H 18 ClN3O2; Impurity II is 4-acetamido-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide, with the molecular formula C 16 H 24 ClN3O3; Impurity III is methyl 4-acetamido-5-chloro-2-methoxybenzoate, with the molecular formula C 11 H 12 ClNO4; Impurity IV is 4-amino-5-chloro-2-methoxybenzoic acid, with the molecular formula C8H8ClNO3; Impurity V is methyl 4-acetamido-2-methoxybenzoate, with the molecular formula C 11 H13 NO4; Impurity VI is N,N-diethylethylenediamine, with the molecular formula C0. 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.

[0106] As can be seen from the above experimental data, compared with Comparative Examples 1-9, the metoclopramide hydrochloride injection prepared in Examples 1-7 of this invention has a lower impurity content and higher stability. The increase in impurity content during the accelerated 3-month and accelerated 6-month tests was significantly lower than that of Comparative Examples 1-9, and no precipitation occurred after 6 months of accelerated storage. In the long-term stability test, the metoclopramide hydrochloride injection provided in this invention showed no precipitation after 24 months of long-term storage, and the impurity content was significantly lower than that of the metoclopramide hydrochloride injections provided in Comparative Examples 1-9. This proves that the metoclopramide hydrochloride injection prepared in this invention has better stability and safety, thus improving the safety of clinical applications.

[0107] 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 or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A metoclopramide hydrochloride injection solution, characterized in that, It includes the following components: metoclopramide, hydrochloric acid solution, hydroxypropyl-γ-cyclodextrin, solubilizer, sodium chloride, pH adjuster and water for injection; The co-solvent includes at least one of alcohol solvents or amide solvents; the alcohol solvent includes at least one of ethanol, propylene glycol, or polyethylene glycol; the amide solvent includes at least one of dimethylformamide or dimethylacetamide. The amount of metoclopramide added is 4.3 mg / mL to 4.6 mg / mL; The hydrochloric acid solution has a mass concentration of 3% to 6%, and the amount of hydrochloric acid solution added is 9 mg / mL to 18 mg / mL. The amount of hydroxypropyl-γ-cyclodextrin added is 11 mg / mL to 13 mg / L; The amount of the co-solvent 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; The pH of the metoclopramide hydrochloride injection solution is 4~7; The preparation method of the metoclopramide hydrochloride injection includes the following steps: S1. Under an inert atmosphere, add 75% to 85% of the prescribed amount of water for injection, metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, solubilizer and sodium chloride to the preparation vessel in sequence and mix. Add water for injection to the total amount to be prepared, add pH adjuster, and obtain metoclopramide hydrochloride solution. S2, the metoclopramide hydrochloride solution is filtered, filled into ampoules under an inert atmosphere, and sterilized to obtain metoclopramide hydrochloride injection.

2. The metoclopramide hydrochloride injection solution as described in claim 1, characterized in that, The co-solvent includes alcohol solvents and amide solvents in a mass ratio of (3~4):

1.

3. A method for preparing the metoclopramide hydrochloride injection solution according to claim 1 or 2, characterized in that, Includes the following steps: S1. Under an inert atmosphere, add 75% to 85% of the prescribed amount of water for injection, metoclopramide, hydroxypropyl-γ-cyclodextrin, hydrochloric acid solution, solubilizer and sodium chloride to the preparation vessel in sequence and mix. Add water for injection to the total amount to be prepared, add pH adjuster, and obtain metoclopramide hydrochloride solution. S2, the metoclopramide hydrochloride solution is filtered, filled into ampoules under an inert atmosphere, and sterilized to obtain metoclopramide hydrochloride injection.

4. The preparation method of metoclopramide hydrochloride injection as described in claim 3, 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%.

5. The preparation method of metoclopramide hydrochloride injection as described in claim 3, characterized in that, In S1~S2, the inert atmosphere is a nitrogen atmosphere or a carbon dioxide atmosphere.

6. The preparation method of metoclopramide hydrochloride injection as described in claim 3, characterized in that, In S2, the filtration uses a two-stage polyethersulfone filter cartridge.

7. The preparation method of metoclopramide hydrochloride injection as described in claim 3, characterized in that, In S2, the sterilization temperature is 120℃~125℃, and the sterilization time is 15min~20min.

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