Citicoline sodium injection and preparation method thereof

Abstract

The invention provides a citicoline sodium injection and a preparation method thereof, and the citicoline sodium injection comprises the following raw materials by weight: 10-15 parts of citicoline sodium, 3-5 parts of phospholipid, 3-5 parts of astaxanthin, 1-3 parts of vitamin C, 0.5-1.5 parts of citric acid, and 900-1100 parts of a solvent. The preparation method comprises the following specific steps: (1) adding phospholipid and citicoline sodium into an ethanol water solution, carrying out ultrasonic treatment, homogenizing and filtering to obtain nano particles embedded with citicoline sodium; (2) adding the citicoline sodium-embedded nanoparticles into a solvent, sequentially adding astaxanthin and vitamin C, performing ultrasonic stirring, adding citric acid, and continuing stirring to obtain a mixed solution; and filtering the mixed solution, sterilizing and filling. The citicoline sodium injection provided by the invention improves the stability to light and oxygen at the same time, and the embodiment verifies that the character and the pH value of the citicoline sodium injection are stable, the content of citicoline sodium is not changed, related substance impurities are few, and the increase of the impurity speed is slow when the citicoline sodium injection is subjected to continuous illumination for 30 days and is placed in an open dark place at 20 DEG C for 30 days respectively.

Description

Technical Field

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

[0002] The main component of Citicoline Sodium Injection is Citicoline Sodium, whose chemical name is the monosodium salt of choline cytosine diphosphate. Citicoline Sodium is a nucleoside derivative. It can reduce cerebral vascular resistance, increase cerebral blood flow, promote brain metabolism, and improve cerebral circulation. It is clinically used to treat acute craniocerebral trauma and consciousness disorders caused by brain surgery. The prior art also discloses many Citicoline Sodium pharmaceutical compositions, especially the preparation methods of its injections, such as patent CN104027304A discloses a Citicoline Sodium Glucose Injection, which is composed of Citicoline Sodium, glucose, glycine, and citric acid. Patent CN102462659A discloses a Citicoline Sodium Injection and its preparation method, which is made from the following formula: Citicoline Sodium 1000-5000g, Disodium Edetate 5g Injection Water 20000ml, 2-5ml per vial. Patent CN106727296B discloses an ambroxol hydrochloride injection and a preparation method thereof, comprising sodium citicoline and a stabilizer, wherein the stabilizer comprises disodium ethylenediaminetetraacetic acid and a pH stabilizer. Patent CN109529016B discloses a sodium citicoline injection and a preparation method thereof, comprising active ingredients, excipients and water for injection, wherein the active ingredients comprise sodium citicoline, disodium cytidine triphosphate, ginsenoside Rg1 and glutathione, and the excipients comprise a stabilizer, an isotonic agent and a pH regulator.

[0003] Citicoline sodium injection is very easy to deteriorate and degrade during the preparation and storage process, so Citicoline sodium needs to be stored and prepared under light-proof and oxygen-proof conditions to reduce its deterioration and degradation. In particular, the preparation process of traditional Citicoline sodium injection usually uses activated carbon filtration, which may cause secondary pollution of drugs and may also adsorb active ingredients, resulting in increased costs. Therefore, the present invention aims to develop a Citicoline sodium injection that does not require activated carbon filtration, has a simple preparation method, is low in cost, and can improve the stability of Citicoline sodium to light and oxygen. Summary of the invention

[0004] In view of this, the present invention provides a citicoline sodium injection and a preparation method thereof.

[0005] The technical solution of the present invention is achieved in this way:

[0006] A citicoline sodium injection comprises the following raw materials, measured by weight percentage: 10-15 parts of citicoline sodium, 3-5 parts of phospholipids, 3-5 parts of astaxanthin, 1-3 parts of vitamin C, 0.5-1.5 parts of citric acid, and 900-1100 parts of solvent.

[0007] Furthermore, the following raw materials are included: 13 parts of citicoline sodium, 4 parts of phospholipids, 4 parts of astaxanthin, 2 parts of vitamin C, 1 part of citric acid, and 1000 parts of solvent.

[0008] Furthermore, the solvent is propylene glycol and water for injection in a volume ratio of (5%-10%): (90%-95%).

[0009] A method for preparing citicoline sodium injection, the specific steps comprising:

[0010] (1) adding phospholipids and citicoline sodium to an ethanol aqueous solution, performing ultrasonic treatment, homogenizing, and filtering to obtain nanoparticles encapsulating citicoline sodium;

[0011] (2) adding nanoparticles encapsulating citicoline sodium into a solvent, adding astaxanthin and vitamin C in sequence, stirring with ultrasound, adding citric acid, and continuing stirring to obtain a mixed solution;

[0012] (3) Filtering, sterilizing, and filling the mixed solution to obtain citicoline sodium injection.

[0013] Furthermore, in step (1), the ethanol aqueous solution is composed of water and ethanol in a volume ratio of 7-9:1-3; and the amount of the ethanol aqueous solution added is 8-12 times the total weight of the phospholipids and citicoline sodium.

[0014] Furthermore, in step (1), the frequency of the ultrasonic wave is 30-40 kHz, the power is 150-250 W, the time is 30-60 min, and the temperature is 20-30°C.

[0015] Furthermore, in step (1), the homogenization speed is 2000-3000 rpm, the time is 2-4 min, and the temperature is 20-30°C.

[0016] Furthermore, in step (2), the speed of the ultrasonic stirring is 400-600 rpm, and the time is 1-2 h; and the time of continued stirring is 20-40 min.

[0017] Furthermore, in step (3), the pH of the citicoline sodium injection is 6.5-7.5.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] 1. The citicoline sodium injection of the present invention has improved stability to light and oxygen at the same time. The examples verify that the properties and pH value are stable within 30 days of continuous illumination, the content of citicoline sodium does not change, the impurities of related substances are less, and the impurity rate increases slowly. After being placed in an open and dark environment at 20°C for 30 days, the properties, pH value, and content of citicoline sodium do not change, the impurities of related substances are less, and the impurity rate increases slowly.

[0020] 2. The astaxanthin of the present invention is a powerful antioxidant, which synergizes with vitamin C to protect citicoline sodium from oxidation and degradation, and can enhance the light and oxygen stability of the injection. Using a specific ratio of propylene glycol and water for injection as a solvent not only significantly improves the solubility of citicoline sodium, but also propylene glycol can be used as a humectant to improve the stability to oxygen. Citric acid not only acts as a pH regulator, but also can be used as a chelating agent to achieve the effect of improving the stability to oxygen.

[0021] 3. The present invention avoids the use of activated carbon filtration in the traditional injection preparation process, and instead uses "ultrasound + homogenization" to embed the original drug of citicoline sodium in lipids, which not only improves the solubility, improves the quality and stability of the injection, and has high safety, but also can reduce the cost of the unit finished product without causing pollution. DETAILED DESCRIPTION

[0022] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0023] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0024] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0025] Example 1

[0026] The raw material formula of citicoline sodium injection in this example is:

[0027] Raw material name quality Citicoline Sodium 13g Phospholipids 4g Astaxanthin 4g Vitamin C 2g Citric Acid 1g Solvents 1000g

[0028] The solvent is propylene glycol and water for injection in a volume ratio of 8%:92%.

[0029] The preparation method of citicoline sodium injection in this embodiment comprises the following specific steps:

[0030] (1) adding phospholipids and citicoline sodium to 170 g of an ethanol aqueous solution with a volume ratio of 8:2, treating under ultrasonic conditions of a frequency of 35 kHz, a power of 200 W, and a temperature of 25° C. for 45 min, homogenizing at a speed of 2500 rpm and a temperature of 25° C. for 3 min, and filtering to obtain nanoparticles encapsulating citicoline sodium;

[0031] (2) adding the nanoparticles encapsulating sodium citicoline to a solvent, adding astaxanthin and vitamin C in sequence, stirring the mixture ultrasonically at a speed of 500 rpm for 1.5 h, adding citric acid, adjusting the pH to 7.0±0.1, and continuing stirring for 30 min to obtain a mixed solution;

[0032] (3) Filtering, sterilizing, and filling the mixed solution to obtain citicoline sodium injection.

[0033] Example 2

[0034] The raw material formula of citicoline sodium injection in this example is:

[0035] Raw material name quality Citicoline Sodium 10g Phospholipids 3g Astaxanthin 3g Vitamin C 1g Citric Acid 0.5g Solvents 900g

[0036] The solvent is propylene glycol and water for injection in a volume ratio of 5%:95%.

[0037] The preparation method of citicoline sodium injection in this embodiment comprises the following specific steps:

[0038] (1) adding phospholipids and citicoline sodium to 104 g of an ethanol aqueous solution with a volume ratio of 7:3, treating under ultrasonic conditions of a frequency of 30 kHz, a power of 150 W, and a temperature of 20° C. for 30 min, and homogenizing at a speed of 2000 rpm and a temperature of 20° C. for 2 min to obtain nanoparticles encapsulating citicoline sodium;

[0039] (2) adding the nanoparticles encapsulating sodium citicoline to a solvent, adding astaxanthin and vitamin C in sequence, stirring ultrasonically at a speed of 400 rpm for 1 h, adding citric acid, adjusting the pH to 6.6±0.1, and continuing stirring for 20 min to obtain a mixed solution;

[0040] (3) Filtering, sterilizing, and filling the mixed solution to obtain citicoline sodium injection.

[0041] Example 3

[0042] The raw material formula of citicoline sodium injection in this example is:

[0043] Raw material name quality Citicoline Sodium 15g Phospholipids 5g Astaxanthin 5g Vitamin C 3g Citric Acid 1.5g Solvents 1100g

[0044] The solvent is propylene glycol and water for injection in a volume ratio of 10%:90%.

[0045] The preparation method of citicoline sodium injection in this embodiment comprises the following specific steps:

[0046] (1) adding phospholipids and citicoline sodium to 240 g of an ethanol aqueous solution with a volume ratio of 9:1, treating under ultrasonic conditions of a frequency of 40 kHz, a power of 250 W, and a temperature of 30° C. for 60 min, and homogenizing at a speed of 3000 rpm and a temperature of 30° C. for 4 min to obtain nanoparticles encapsulating citicoline sodium;

[0047] (2) adding the nanoparticles encapsulating sodium citicoline to a solvent, adding astaxanthin and vitamin C in sequence, stirring ultrasonically at 600 rpm for 2 h, adding citric acid, adjusting the pH to 7.4±0.1, and continuing stirring for 40 min to obtain a mixed solution;

[0048] (3) Filtering, sterilizing, and filling the mixed solution to obtain citicoline sodium injection.

[0049] Comparative Example 1

[0050] The difference from Example 1 is that the amount of raw materials is different, and the rest is consistent with Example 1.

[0051] The raw material formula of citicoline sodium injection in this comparative example is:

[0052]

[0053]

[0054] Comparative Example 2

[0055] The difference from Example 1 is that the solvent lacks propylene glycol, that is, the solvent only contains water for injection, and the rest is consistent with Example 1.

[0056] The raw material formula of citicoline sodium injection in this comparative example is:

[0057] Raw material name quality Citicoline Sodium 13g Phospholipids 4g Astaxanthin 4g Vitamin C 2g Citric Acid 1g Water for injection 1000g

[0058] The preparation method of the citicoline sodium injection in this comparative example comprises the following specific steps:

[0059] (1) adding phospholipids and citicoline sodium to 170 g of an ethanol aqueous solution with a volume ratio of 8:2, treating under ultrasonic conditions of a frequency of 35 kHz, a power of 200 W, and a temperature of 25° C. for 45 min, homogenizing at a speed of 2500 rpm and a temperature of 25° C. for 3 min, and filtering to obtain nanoparticles encapsulating citicoline sodium;

[0060] (2) adding the nanoparticles encapsulating sodium citicoline to water for injection, adding astaxanthin and vitamin C in sequence, stirring ultrasonically at a speed of 500 rpm for 1.5 h, adding citric acid, adjusting the pH to 7.0±0.1, and continuing stirring for 30 min to obtain a mixed solution;

[0061] (3) Filtering, sterilizing, and filling the mixed solution to obtain citicoline sodium injection.

[0062] Comparative Example 3

[0063] The difference from Example 1 is that sodium dihydrogen phosphate is used instead of citric acid, and the rest is the same as Example 1.

[0064] The raw material formula of citicoline sodium injection in this comparative example is:

[0065]

[0066]

[0067] The solvent is propylene glycol and water for injection in a volume ratio of 8%:92%.

[0068] The preparation method of the citicoline sodium injection in this comparative example comprises the following specific steps:

[0069] (1) adding phospholipids and citicoline sodium to 170 g of an ethanol aqueous solution with a volume ratio of 8:2, treating under ultrasonic conditions of a frequency of 35 kHz, a power of 200 W, and a temperature of 25° C. for 45 min, homogenizing at a speed of 2500 rpm and a temperature of 25° C. for 3 min, and filtering to obtain nanoparticles encapsulating citicoline sodium;

[0070] (2) adding the nanoparticles encapsulating sodium citicoline to a solvent, adding astaxanthin and vitamin C in sequence, stirring ultrasonically at a speed of 500 rpm for 1.5 h, adding sodium dihydrogen phosphate, adjusting the pH to 7.0±0.1, and continuing stirring for 30 min to obtain a mixed solution;

[0071] (3) Filtering, sterilizing, and filling the mixed solution to obtain citicoline sodium injection.

[0072] Comparative Example 4

[0073] The difference from Example 1 is that astaxanthin is missing, that is, 4 g of astaxanthin is distributed to other components in proportion, and the rest is consistent with Example 1.

[0074] The raw material formula of citicoline sodium injection in this comparative example is:

[0075] Raw material name quality Citicoline Sodium 15.6g Phospholipids 4.8g Vitamin C 2.4g Citric Acid 1.2g Solvents 1000g

[0076] The solvent is propylene glycol and water for injection in a volume ratio of 8%:92%.

[0077] The preparation method of the citicoline sodium injection in this comparative example comprises the following specific steps:

[0078] (1) adding phospholipids and citicoline sodium to 170 g of an ethanol aqueous solution with a volume ratio of 8:2, treating under ultrasonic conditions of a frequency of 35 kHz, a power of 200 W, and a temperature of 25° C. for 45 min, homogenizing at a speed of 2500 rpm and a temperature of 25° C. for 3 min, and filtering to obtain nanoparticles encapsulating citicoline sodium;

[0079] (2) adding the nanoparticles encapsulating citicoline sodium to a solvent, adding vitamin C, stirring ultrasonically at a speed of 500 rpm for 1.5 h, adding citric acid, adjusting the pH to 7.0±0.1, and continuing stirring for 30 min to obtain a mixed solution;

[0080] (3) Filtering, sterilizing, and filling the mixed solution to obtain citicoline sodium injection.

[0081] Comparative Example 5

[0082] The difference from Example 1 is that the preparation method is different, and the rest is consistent with Example 1.

[0083] The preparation method of the citicoline sodium injection in this comparative example comprises the following specific steps:

[0084] Add phospholipids, sodium citicoline, astaxanthin and vitamins to 800 g of solvent, stir to dissolve, add citric acid, adjust the pH to 7.0±0.1, add 1 g of activated carbon, stir and adsorb for 30 min, decarbonize and filter, add 200 g of solvent, stir for 30 min, filter, sterilize and fill to obtain sodium citicoline injection.

[0085] Photostability test

[0086] The citicoline sodium injections prepared in Examples 1-3 and Comparative Examples 1-5 were placed under strong light conditions of 5000 lx for 10 days and 30 days, and compared with 0 day, and the properties, pH, citicoline sodium content, and the content of related impurities were measured. The content of citicoline sodium = the content of citicoline sodium in the sample to be tested / the content of citicoline sodium in the initial sample × 100%. The results are shown in Table 1.

[0087] Table 1

[0088]

[0089]

[0090] As can be seen from Table 1, the citicoline sodium injection prepared by the present invention can improve the stability to light. Under continuous strong light irradiation for 30 days, the properties and pH value are stable, the content of citicoline sodium does not change, the impurities of related substances are less, and the impurity rate increases slowly. Compared with Example 1, the citicoline sodium injection prepared by Comparative Examples 1-5 changes in properties, pH value and citicoline sodium content under continuous light irradiation for 30 days, indicating that the stability to light is deteriorated, the impurities of related substances increase, and the impurity rate increases faster.

[0091] Oxygen stability test

[0092] 200 mL of citicoline sodium injection prepared in the above Examples 1-3 and Comparative Examples 1-5 were taken and placed in an open and dark environment at 20° C. for 15 days and 30 days, and then compared with 0 day to measure the properties, pH, citicoline sodium content, and impurity content of related substances. The content of citicoline sodium = the content of citicoline sodium in the sample to be tested / the content of citicoline sodium in the initial sample × 100%. The results are shown in Table 2.

[0093] Table 2

[0094]

[0095]

[0096] As can be seen from Table 2, the Citicoline Sodium Injection prepared by the present invention can improve the stability to oxygen. After being exposed to light for 30 days, no precipitation or deterioration occurs, the pH value is stable, the content of Citicoline Sodium does not change, the impurities of related substances are less, and the impurity rate increases slowly. Compared with Example 1, the Citicoline Sodium Injections prepared in Comparative Examples 1-5 produce precipitation and deterioration, pH changes, the content of Citicoline Sodium changes, the impurities of related substances are more, and the impurity rate increases faster after being exposed to light for 30 days, indicating that the stability to oxygen is poor.

[0097] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A citicoline sodium injection, characterized in that: The invention comprises the following raw materials in parts by weight: 10-15 parts of sodium citicoline, 3-5 parts of phospholipids, 3-5 parts of astaxanthin, 1-3 parts of vitamin C, 0.5-1.5 parts of citric acid and 900-1100 parts of solvent.

2. A citicoline sodium injection according to claim 1, characterized in that: The invention comprises the following raw materials: 13 parts of citicoline sodium, 4 parts of phospholipids, 4 parts of astaxanthin, 2 parts of vitamin C, 1 part of citric acid and 1000 parts of solvent.

3. A citicoline sodium injection according to claim 1, characterized in that: The solvent is propylene glycol and water for injection in a volume ratio of (5%-10%):(90%-95%).

4. The method for preparing citicoline sodium injection according to claim 1, characterized in that: The specific steps include: (1) adding phospholipids and citicoline sodium to an ethanol aqueous solution, performing ultrasonic treatment, homogenizing, and filtering to obtain nanoparticles encapsulating citicoline sodium; (2) adding nanoparticles encapsulating citicoline sodium into a solvent, adding astaxanthin and vitamin C in sequence, stirring with ultrasound, adding citric acid, and continuing stirring to obtain a mixed solution; (3) Filtering, sterilizing, and filling the mixed solution to obtain citicoline sodium injection.

5. The method for preparing citicoline sodium injection according to claim 1, characterized in that: In step (1), the ethanol aqueous solution is composed of water and ethanol in a volume ratio of 7-9:1-3; the amount of the ethanol aqueous solution added is 8-12 times the total weight of the phospholipids and citicoline sodium.

6. The method for preparing citicoline sodium injection according to claim 1, characterized in that: In step (1), the frequency of the ultrasonic wave is 30-40kHz, the power is 150-250W, the time is 30-60min, and the temperature is 20-30°C.

7. The method for preparing citicoline sodium injection according to claim 1, characterized in that: In step (1), the homogenization speed is 2000-3000 rpm, the time is 2-4 min, and the temperature is 20-30°C.

8. The method for preparing citicoline sodium injection according to claim 1, characterized in that: In step (2), the speed of the ultrasonic stirring is 400-600 rpm, and the time is 1-2 hours; the time of continued stirring is 20-40 minutes.

9. The method for preparing citicoline sodium injection according to claim 1, characterized in that: In step (3), the pH of the citicoline sodium injection is 6.5-7.5.

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