Amisulpride injection and preparation method thereof

Abstract

The invention relates to the technical field of medicines, and particularly discloses an amisulpride injection and a preparation method thereof. The amisulpride injection is prepared from the following raw materials in parts by weight: 30 to 50 parts of amisulpride, 500 to 700 parts of water for injection, 3 to 5 parts of an antioxidant, 0.5 to 1 part of an osmotic pressure regulator, a pH regulator for regulating the pH value to 4.0 to 7.0 and 100 to 200 parts of a cosolvent, according to the prepared amisulpride injection, the cosolvent and the water for injection are combined, so that the dissolution of the amisulpride is accelerated, the bioavailability of the amisulpride injection is improved, and meanwhile, the antioxidant and the osmotic pressure regulator are combined, so that the stability and the oxidation resistance of the amisulpride injection are improved.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to an amisulpride injection and a preparation method thereof. Background Art

[0002] Amisulpride is a psychotherapeutic drug mainly used to treat mental illnesses such as schizophrenia. At present, amisulpride is mainly used in the form of oral tablets. However, amisulpride has extremely low solubility and is not easily soluble in water. Oral drugs have poor absorption, so it is necessary to develop an amisulpride injection.

[0003] However, the traditional amisulpride injection has poor stability and is prone to oxidation reactions. In the presence of oxygen, it can easily lead to changes in the molecular structure of the drug and affect its efficacy and stability. Summary of the invention

[0004] In order to improve the problem of poor stability of the existing amisulpride injection, the present application provides an amisulpride injection and a preparation method thereof.

[0005] In the first aspect, the present application provides an amisulpride injection, which adopts the following technical solution: An amisulpride injection comprises the following raw materials in parts by weight: 30-50 parts of amisulpride, 500-700 parts of water for injection, 3-5 parts of an antioxidant, 0.5-1 part of an osmotic pressure regulator, a pH regulator whose pH value is adjusted to 4.0-7.0, and 100-200 parts of a solvent.

[0006] By adopting the above technical scheme, a cosolvent is used in combination with water for injection to promote the dissolution of amisulpride, and it is also convenient for human body absorption, thereby improving the absorption and utilization effect of amisulpride injection. Antioxidants are used to reduce the oxidation reaction of amisulpride and improve the stability of amisulpride injection. Adding an appropriate amount of osmotic pressure regulator to the raw material of amisulpride injection can maintain the osmotic pressure stability of amisulpride injection, reduce the discomfort of local tissues and the destruction of cell membranes caused by amisulpride injection after injection into the body, and improve the bioavailability and absorption effect of amisulpride injection. At the same time, the osmotic pressure regulator can reduce the precipitation and phase separation of amisulpride drugs in the injection, reduce the decomposition or degradation reaction of drugs caused by improper osmotic pressure, and then improve the uniformity and stability of amisulpride injection.

[0007] Preferably, the cosolvent is one of polyethylene glycol and dimethylacetamide.

[0008] By adopting the above technical solution, polyethylene glycol and dimethylacetamide can form hydrogen bonding forces with the active components of the drug, thereby improving the solubility of amisulpride in the injection, reducing the interaction between drug molecules, improving the solubility of amisulpride and the drug stability of amisulpride injection. Polyethylene glycol and dimethylacetamide can improve the transportability of amisulpride injection, making it easier for amisulpride to be injected into tissues and cells in the human body, while also reducing the adverse effects of amisulpride injection on human cells and tissues, and improving the bioavailability and stability of amisulpride injection.

[0009] Preferably, the pH adjuster is at least one of hydrochloric acid, citric acid, sodium citrate, lactic acid, disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0010] By adopting the above technical solution, hydrochloric acid, citric acid, sodium citrate, lactic acid, disodium hydrogen phosphate and sodium dihydrogen phosphate are added to amisulpride injection as pH regulators, the pH of amisulpride injection can be maintained within a reasonable range, the occurrence of drug decomposition or degradation reactions can be reduced, and the efficiency and safety of the drug can be maintained. At the same time, by adjusting the pH of amisulpride injection, the solubility of the drug can be increased, and the uniformity and stability of amisulpride in the injection can be improved. At the same time, the appropriate pH can reduce the pain or irritation that may be caused during the injection process and improve the patient's acceptance.

[0011] Preferably, the osmotic pressure regulator is at least one of sodium chloride, sodium lactate, glucose and β-cyclodextrin.

[0012] By adopting the above technical solution, sodium lactate can play a role in regulating osmotic pressure, and at the same time can also improve the additional acid-base balance function to maintain the stability and solubility of amisulpride in the injection. Sodium chloride can adjust the osmotic pressure of the injection, and can reduce the damage or water loss of cells due to osmotic pressure differences. Glucose can regulate the osmotic pressure of amisulpride injection, and can also be used as a nutritional supplement for the drug to provide energy. β-cyclodextrin can regulate the osmotic pressure of the injection, and at the same time can regulate the solubility and stability of amisulpride, and improve the bioavailability and stability of amisulpride.

[0013] Preferably, the osmotic pressure regulator is a mixture of β-cyclodextrin and sodium chloride.

[0014] Preferably, the antioxidant is one of sulfurous acid, sodium bisulfite and vitamin C.

[0015] By adopting the above technical solution, sulfurous acid has good reducing property, can effectively react with oxygen, capture oxygen molecules in the injection to reduce the oxidation of amisulpride components, and improve the stability of amisulpride in the injection. Sodium bisulfite and vitamin C are effective antioxidants. Sodium bisulfite can provide hydrogen ions and sulfite ions to react with oxygen, and vitamin C can directly react with free radicals and peroxides to reduce the oxidation and degradation of amisulpride drugs, improve the stability and activity of amisulpride injection, and extend the shelf life of amisulpride drugs in Yancheng, ensuring the effectiveness and safety of amisulpride injection.

[0016] Preferably, the raw materials of amisulpride injection also include 1-3 parts of ethylenediaminetetraacetic acid.

[0017] By adopting the above technical solution, EDTA can form a stable chelate with the impurity metal ions in amisulpride injection, reduce the oxidation reaction catalyzed by metal ions, reduce the free concentration of metal ions, and thus protect the amisulpride components from being oxidized and degraded, thereby improving the antioxidant and stability of amisulpride injection. Ethylenediaminetetraacetic acid can reduce the consumption of metal ions on sulfurous acid, sodium bisulfite, and vitamin C antioxidants by chelating metal ions, thereby improving the antioxidant properties of amisulpride injection.

[0018] In a second aspect, the present application provides a method for preparing amisulpride injection, using the following technical solution: A method for preparing amisulpride injection comprises the following specific steps: Antioxidants, osmotic pressure regulators and co-solvents are added to water for injection in advance, the mixture is heated to 40-50°C, and stirred evenly to form a mixed solution. Amisulpride is then added to the mixed solution, and the pH value of the mixed solution is adjusted to 4.0-7.0 using a pH regulator. The mixture is then filtered and sterilized at high temperature to obtain amisulpride injection.

[0019] By adopting the above technical solution, the solubility of amisulpride can be improved by appropriately heating the temperature of the mixed solution, and then the pH value of the mixed solution is adjusted using a pH regulator, which is beneficial to improving the stability of amisulpride injection.

[0020] Preferably, the filter membrane has a size of 0.2-0.5 μm.

[0021] In summary, this application has the following beneficial effects: 1. Since the present application uses an antioxidant to reduce the oxidation reaction of amisulpride, the stability of amisulpride injection is improved. At the same time, the osmotic pressure regulator is used to maintain the osmotic pressure stability of amisulpride injection, and improve the bioavailability and absorption effect of amisulpride drugs in the human body. At the same time, the osmotic pressure regulator can reduce the drug decomposition or degradation reaction of amisulpride, and improve the uniformity and stability of amisulpride injection.

[0022] 2. In this application, hydrochloric acid, citric acid, sodium citrate, lactic acid, disodium hydrogen phosphate and sodium dihydrogen phosphate are used as pH regulators to adjust the pH of amisulpride injection within an appropriate range, reduce the decomposition or degradation of the drug, increase the solubility of amisulpride, and improve the uniformity and stability of amisulpride injection. DETAILED DESCRIPTION

[0023] The present application is further described in detail below in conjunction with embodiments.

[0024] All raw materials in the examples are commercially available. Example

[0025] Example 1 This embodiment provides an amisulpride injection, comprising the following raw materials in parts by weight: 40 g amisulpride, 600 g water for injection, 4 g antioxidant, 0.8 g osmotic pressure regulator, 150 g cosolvent, and a pH regulator to adjust the pH value to 6. The cosolvent is dimethylacetamide, the antioxidant is sulfurous acid, the osmotic pressure regulator is sodium chloride, and the pH regulator is citric acid and sodium citrate.

[0026] The preparation method of amisulpride injection comprises the following specific steps: Add antioxidant, osmotic pressure regulator and co-solvent to water for injection, mix, heat to 45°C, stir evenly to form a mixed solution, then add amisulpride to the mixed solution while keeping warm, stir at a stirring speed of 80 r / min until amisulpride is fully dissolved, record the time for amisulpride to dissolve, then use a pH regulator to adjust the pH value of the mixed solution to 6, then filter through a 0.3 μm filter membrane, and sterilize at high temperature to obtain amisulpride injection.

[0027] Example 2 The difference between Example 2 and Example 1 is that the amount of amisulpride used in the amisulpride injection raw material is 30g, the amount of water for injection is 500g, the amount of antioxidant is 3g, the amount of osmotic pressure regulator is 0.5g, and the amount of cosolvent is 100g.

[0028] Example 3 The difference between Example 3 and Example 1 is that the amount of amisulpride used in the amisulpride injection raw material is 50g, the amount of water for injection is 700g, the amount of antioxidant is 5g, the amount of osmotic pressure regulator is 1g, and the amount of cosolvent is 200g.

[0029] Example 4 The difference between Example 4 and Example 1 is that the pH regulator in the raw materials of amisulpride injection is disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0030] Example 5 The difference between Example 5 and Example 1 is that the osmotic pressure regulator in the raw material of amisulpride injection is sodium lactate.

[0031] Example 6 The difference between Example 6 and Example 1 is that the osmotic pressure regulator in the raw material of amisulpride injection is a mixture of β-cyclodextrin and sodium chloride, and the mass ratio of β-cyclodextrin to sodium chloride is 1:1.

[0032] The preparation method of amisulpride injection comprises the following specific steps: β-cyclodextrin and sodium chloride are mixed in advance, stirred evenly to form an osmotic pressure regulator, and then an antioxidant, an osmotic pressure regulator, and a cosolvent are added to water for injection, the mixture is heated to 45°C, and stirred evenly to form a mixed solution, and then amisulpride is added to the mixed solution under insulation, and stirred at a stirring speed of 80 r / min until amisulpride is fully dissolved, and the dissolution time of amisulpride is recorded, and then a pH regulator is used to adjust the pH value of the mixed solution to 6, and then filtered through a 0.3 μm filter membrane, and then sterilized at high temperature to obtain amisulpride injection.

[0033] Example 7 The difference between Example 7 and Example 6 is that the antioxidant in the raw material of amisulpride injection is vitamin C.

[0034] Example 8 The difference between Example 8 and Example 7 is that the raw materials of amisulpride injection further include 2 g of ethylenediaminetetraacetic acid.

[0035] The preparation method of amisulpride injection comprises the following specific steps: β-cyclodextrin and sodium chloride are mixed in advance, stirred evenly to form an osmotic pressure regulator, and then an antioxidant, an osmotic pressure regulator, ethylenediaminetetraacetic acid, and a cosolvent are added to water for injection, the mixture is heated to 45°C, stirred evenly to form a mixed solution, and then amisulpride is added to the mixed solution under insulation, and stirred at a stirring speed of 80 r / min until amisulpride is fully dissolved, the dissolution time of amisulpride is recorded, and then a pH regulator is used to adjust the pH value of the mixed solution to 6, and then filtered through a 0.3 μm filter membrane, and then sterilized at high temperature to obtain amisulpride injection.

[0036] Example 9 The difference between Example 9 and Example 8 is that the amount of EDTA used in the raw material of amisulpride injection is 1 g.

[0037] Example 10 The difference between Example 10 and Example 8 is that the amount of EDTA used in the raw material of amisulpride injection is 3 g.

[0038] Comparative Example Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that no antioxidant is used in the raw materials of amisulpride injection.

[0039] The preparation method of amisulpride injection comprises the following specific steps: An osmotic pressure regulator and a cosolvent are added to water for injection, the mixture is heated to 45°C, and stirred evenly to form a mixed solution. Amisulpride is then added to the mixed solution while keeping the temperature constant. The mixture is stirred at a stirring speed of 80 r / min until the amisulpride is fully dissolved. The dissolution time of amisulpride is recorded. The pH value of the mixed solution is then adjusted to 6 using a pH regulator. The mixture is then filtered through a 0.3 μm filter membrane and sterilized at high temperature to obtain amisulpride injection.

[0040] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that no osmotic pressure regulator is used in the raw materials of amisulpride injection.

[0041] The preparation method of amisulpride injection comprises the following specific steps: Add antioxidant and co-solvent to water for injection, mix, heat to 45°C, stir evenly to form a mixed solution, then add amisulpride to the mixed solution while keeping warm, stir at a stirring speed of 80 r / min until amisulpride is fully dissolved, record the time for amisulpride to dissolve, then use a pH adjuster to adjust the pH value of the mixed solution to 6, then filter through a 0.3 μm filter membrane, and sterilize at high temperature to obtain amisulpride injection.

[0042] Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that no co-solvent is used in the raw materials of amisulpride injection.

[0043] The preparation method of amisulpride injection comprises the following specific steps: An osmotic pressure regulator and an antioxidant are added to water for injection, the mixture is heated to 45°C, and stirred evenly to form a mixed solution. Amisulpride is then added to the mixed solution while keeping the temperature constant. The mixture is stirred at a stirring speed of 80 r / min until the amisulpride is fully dissolved. The dissolution time of amisulpride is recorded. The pH value of the mixed solution is then adjusted to 6 using a pH regulator. The mixture is then filtered through a 0.3 μm filter membrane and sterilized at high temperature to obtain amisulpride injection.

[0044] Performance testing The following performance tests were performed on the amisulpride injection provided in Examples 1-10 and Comparative Examples 1-3 of the present application. The specific test results are shown in Table 1.

[0045] Detection Methods 1. Solubility The dissolution time of amisulpride was recorded to detect the solubility of the amisulpride injection prepared in the present application.

[0046] 2. Stability The amisulpride injection prepared in the present application was placed in a constant temperature and humidity chamber at 40°C, and samples were taken on the 5th and 10th days. The amisulpride content in the samples was detected by high performance liquid chromatography, and the change in the amisulpride content was determined compared with that on the 0th day.

[0047] Table 1: Performance test results data table It can be seen from the performance test results that the amisulpride injection prepared in the present application accelerates the dissolution of amisulpride by using a cosolvent in combination with water for injection, making it easier for the amisulpride injection to be absorbed by the human body. At the same time, antioxidants and osmotic pressure regulators are used to improve the stability of the amisulpride injection, reduce the oxidative decomposition of the amisulpride drug, and improve the bioavailability and absorption effect of the amisulpride injection.

[0048] By comparing Example 4 with Example 1, it can be seen that Example 4 uses a different pH regulator, and from the performance test results, it can be seen that the solubility of the amisulpride injection prepared in Example 4 is slightly better.

[0049] By comparing Example 6 with Example 1, it can be seen that the osmotic pressure regulator in the raw material of amisulpride injection in Example 6 is a mixture of β-cyclodextrin and sodium chloride, and the performance test results show that the solubility and stability of amisulpride injection prepared in Example 6 are better. This may be because both sodium chloride and β-cyclodextrin can better adjust the osmotic pressure of the injection, and β-cyclodextrin has a good hydrophilic effect and can be coated on the surface of amisulpride to improve the solubility of amisulpride.

[0050] By comparing Examples 8-10 with Example 1, it can be seen that in Examples 8-10, different amounts of EDTA are added to the raw materials of amisulpride injection, and the solubility and stability of amisulpride injection are further increased as shown in the performance test results. This further illustrates that EDTA can form stable chelates with metal ions, reduce the phenomenon of amisulpride being oxidized by metal ions, and improve the stability of amisulpride injection.

[0051] By comparing Comparative Examples 1-3 with Example 1, it can be seen that no antioxidant is used in the raw material of amisulpride injection in Comparative Example 1, no osmotic pressure regulator is used in the raw material of amisulpride injection in Comparative Example 2, and no cosolvent is used in the raw material of amisulpride injection in Comparative Example 3. It can be seen from the performance test results that the solubility and stability of amisulpride injection are significantly reduced, especially in the amisulpride injection prepared in Comparative Example 3, the dissolution effect of amisulpride is poor, and the stability of the prepared amisulpride injection is also low, and the shelf life is short.

[0052] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. An amisulpride injection, characterized in that: The invention comprises the following raw materials in parts by weight: 30-50 parts of amisulpride, 500-700 parts of injection water, 3-5 parts of antioxidant, 0.5-1 part of osmotic pressure regulator, pH regulator for regulating pH value to 4.0-7.0, and 100-200 parts of cosolvent.

2. Amisulpride injection according to claim 1, characterized in that: The cosolvent is one of polyethylene glycol and dimethylacetamide.

3. Amisulpride injection according to claim 1, characterized in that: The pH adjuster is at least one of hydrochloric acid, citric acid, sodium citrate, lactic acid, disodium hydrogen phosphate and sodium dihydrogen phosphate.

4. Amisulpride injection according to claim 1, characterized in that: The osmotic pressure regulator is at least one of sodium chloride, sodium lactate, glucose and β-cyclodextrin.

5. Amisulpride injection according to claim 4, characterized in that: The osmotic pressure regulator is a mixture of β-cyclodextrin and sodium chloride.

6. Amisulpride injection according to claim 1, characterized in that: The antioxidant is one of sulfurous acid, sodium bisulfite and vitamin C.

7. Amisulpride injection according to claim 6, characterized in that: The raw materials of the amisulpride injection also include 1-3 parts of ethylenediaminetetraacetic acid.

8. A method for preparing amisulpride injection as claimed in claims 1-7, characterized in that: The specific steps include: Antioxidants, osmotic pressure regulators and co-solvents are added to water for injection in advance, the mixture is heated to 40-50°C, and stirred evenly to form a mixed solution. Amisulpride is then added to the mixed solution, and the pH value of the mixed solution is adjusted to 4.0-7.0 using a pH regulator. The mixture is then filtered and sterilized at high temperature to obtain amisulpride injection.

9. The method for preparing amisulpride injection according to claim 8, characterized in that: The filter membrane size is 0.2-0.5 μm.

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