Vitamin B6 injection and preparation method thereof

Abstract

The invention provides a vitamin B6 injection and a preparation method thereof. The vitamin B6 injection is prepared from the following raw materials in parts by weight: 10 to 15 parts of vitamin B6 nanocrystals, 0.5 to 0.8 part of water-soluble fullerene, 1 to 2 parts of tetrahydromethylpyrimidine carboxylic acid, 0.8 to 1 part of a polyglutamic acid-polyethylene glycol compound, 1 to 3 parts of a pH (Potential of Hydrogen) regulator and 100 to 200 parts of water for injection. The vitamin B6 injection provided by the invention has high stability, and the storage time is prolonged to 48 months from the traditional 12 months. Most importantly, a part of the vitamin B6 nanocrystals are loaded on the water-soluble fullerene, a part of the vitamin B6 nanocrystals are coated on the polyglutamic acid-polyethylene glycol compound, and the components are separately prepared and then mixed, so that the prepared vitamin B6 injection is difficult to decompose under illumination and resistant to high temperature, and after an accelerated experiment process, the clarity, pH, content and impurities of the vitamin B6 injection are stable; no obvious change exists, and the application prospect is wide.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a vitamin B6 injection and a preparation method thereof. Background Art

[0002] Vitamin B6 is a colorless crystal that is easily soluble in water and ethanol. It is also called pyridoxine, which includes pyridoxine, pyridoxal and pyridoxamine. It exists in the body in the form of phosphate esters. It is a water-soluble vitamin that is easily destroyed by light or alkali and is not resistant to high temperatures. Vitamin B6 is a component of certain coenzymes in the human body and participates in a variety of metabolic reactions, especially amino acid metabolism. Clinical application of vitamin B6 preparations can prevent and treat pregnancy vomiting, radiation vomiting, seborrheic dermatitis, etc.

[0003] The preparation process of vitamin B6 injection is generally to dissolve vitamin B6 in the injection water after cooling, sterile filtration and filling, inspection, and packaging. However, the vitamin B6 injection obtained by this process has poor stability, especially after the accelerated test process, its clarity and stability are obviously reduced. Therefore, vitamin B6 injection has the common problems of short storage time and poor stability. In addition, vitamin B6 injection is easy to decompose when exposed to light and is not resistant to high temperature, so it is necessary to avoid light during preparation, storage, transportation and use.

[0004] Therefore, it is necessary to develop a vitamin B6 injection with high stability, whose properties (clarity, pH, content, impurities) remain unchanged and stability does not change significantly after accelerated experiments under light and high temperature conditions, which has practical significance. Summary of the invention

[0005] In view of this, the present invention provides a vitamin B6 injection and a preparation method thereof to overcome the shortcomings of the existing vitamin B6 injection.

[0006] The technical solution of the present invention is achieved in this way:

[0007] A vitamin B6 injection comprises the following raw materials in parts by weight: 10-15 parts of vitamin B6 nanocrystals, 0.5-0.8 parts of water-soluble fullerenes, 1-2 parts of tetrahydromethylpyrimidine carboxylic acid, 0.8-1 parts of polyglutamic acid-polyethylene glycol complex, 1-3 parts of pH regulator, and 100-200 parts of water for injection.

[0008] Furthermore, the particle size of the vitamin B6 nanocrystals is 100-150nm.

[0009] Furthermore, the particle size of the polyglutamic acid-polyethylene glycol complex is 200-300 nm.

[0010] Furthermore, the method for preparing the vitamin B6 nanocrystals includes: adding vitamin B6 to deionized water, ultrasonic treatment, freezing, vacuum drying, and grinding to obtain vitamin B6 nanocrystals.

[0011] Furthermore, the solid-liquid ratio of vitamin B6 to ionized water is 1:10-20 mg / mL; the ultrasonic treatment is performed at 50-100 rpm and 20-25°C for 5-10 min; the freezing temperature is minus 20°C to minus 10°C; the vacuum drying pressure is 20-50 Pa, and the time is 8-12 h.

[0012] Furthermore, the preparation method of the polyglutamic acid-polyethylene glycol complex comprises: adding polyglutamic acid and polyethylene glycol into water, ultrasonic treatment, adding glutaraldehyde for cross-linking reaction, centrifugation, washing and drying to obtain the polyglutamic acid-polyethylene glycol complex.

[0013] Furthermore, the mass ratio of polyglutamic acid to polyethylene glycol is 1:1-5; the amount of water added is 10-15 times the total mass of polyglutamic acid and polyethylene glycol; the ultrasonic treatment is carried out at 20-30kHz, 30-40°C for 20-30min; the concentration of glutaraldehyde is 0.1%-0.3% w / v; the mass ratio of polyglutamic acid to glutaraldehyde is 1:0.1-0.3; and the cross-linking reaction is carried out at 30-40°C for 2-4h.

[0014] A method for preparing vitamin B6 injection, the specific steps comprising:

[0015] (1) adding water-soluble fullerene to injection water in a formula amount of 20-30 wt% and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding vitamin B6 nanocrystals in a formula amount of 40-50 wt%, stirring evenly, and obtaining a mixed solution a;

[0016] (2) adding the polyglutamic acid-polyethylene glycol complex to 20-30 wt% injection water and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding the remaining amount of vitamin B6 nanocrystals, stirring evenly, and obtaining a mixed solution b;

[0017] (3) Mix the mixed solution a and the mixed solution b, make up the remaining volume with water for injection, add a pH adjuster to adjust the pH to 2-3, filter through a microporous membrane for the first time, add tetrahydromethylpyrimidine carboxylic acid, filter through a microporous membrane again, sterilize, and fill to obtain a vitamin B6 injection solution.

[0018] Furthermore, in steps (1) and (2), the stirring speed is 100-200 rpm and the time is 1-3 h.

[0019] Furthermore, in step (3), the pore size of the first microporous membrane filtration is 0.4-0.5 μm; and the pore size of the second microporous membrane filtration is 0.20-0.22 μm.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1. The vitamin B6 injection prepared by the present invention has high stability, and the storage time is extended from the traditional 12 months to 48 months. Most importantly, the vitamin B6 injection of the present invention is not easy to decompose under light, is resistant to high temperatures, and after the accelerated experimental process, its clarity, pH, content, and impurities are stable without obvious changes, and has broad application prospects.

[0022] 2. The present invention uses water-soluble fullerene not only as a carrier for loading vitamin B6 nanocrystals, improving the absorption and utilization of drugs, reducing patient compliance, having good biocompatibility and being harmless to the body, but also as a good antioxidant, protecting vitamin B6 from degradation caused by light and oxidation, and improving the stability of drugs.

[0023] 3. The vitamin B6 nanocrystals of the present invention can improve the solubility and absorption rate of vitamin B6 and enhance stability.

[0024] 4. The present invention uses a polyglutamic acid-polyethylene glycol complex to coat vitamin B6 nanocrystals, which not only enhances the targeted delivery effect of vitamin B6, but also forms a more stable complex and improves the overall performance of the vitamin B6 injection.

[0025] 5. The present invention uses tetrahydromethylpyrimidine carboxylic acid as a stabilizer and antioxidant to form a protective layer and increase the stability of the drug.

[0026] 6. The preparation process of the present invention loads a portion of the vitamin B6 nanocrystals on water-soluble fullerenes, and a portion of the vitamin B6 nanocrystals are coated on a polyglutamic acid-polyethylene glycol complex, which are prepared separately and then mixed to avoid drug adhesion during subsequent treatment. DETAILED DESCRIPTION

[0027] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0028] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0029] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0030] In the present invention, water-soluble fullerene is added into injection water to form a light yellow transparent liquid.

[0031] The water-soluble fullerene of the present invention was purchased from Wuhan Kemik Biopharmaceutical Technology Co., Ltd.

[0032] The tetrahydromethylpyrimidine carboxylic acid (pharmaceutical grade) of the present invention was purchased from Hubei Rishengchang New Material Technology Co., Ltd.

[0033] Example 1

[0034] A vitamin B6 injection comprises the following raw materials in parts by weight: 13 parts of vitamin B6 nanocrystals, 0.7 parts of water-soluble fullerenes, 1.5 parts of tetrahydromethylpyrimidine carboxylic acid, 0.9 parts of polyglutamic acid-polyethylene glycol complex, 2 parts of pH regulators, and 150 parts of water for injection.

[0035] Preparation of vitamin B6 nanocrystals: Vitamin B6 was added to deionized water at a solid-liquid ratio of 1:15 mg / mL, ultrasonically treated at 75 rpm and 23°C for 8 min, frozen at -15°C, vacuum dried at 35 Pa for 10 h, and ground to obtain vitamin B6 nanocrystals with a particle size of 135 nm.

[0036] Preparation of polyglutamic acid-polyethylene glycol complex: polyglutamic acid and polyethylene glycol in a mass ratio of 1:3 are added to water (the amount of water added is 13 times the total mass of polyglutamic acid and polyethylene glycol), ultrasonically treated at 25kHz, 35°C for 25min, 0.2% w / v glutaraldehyde is added (the mass ratio of glutaraldehyde to polyglutamic acid is 0.2:1), and the cross-linking reaction is continued at 35°C for 3h. Centrifuge, wash and dry to obtain a polyglutamic acid-polyethylene glycol complex with a particle size of 250nm.

[0037] The preparation method of the above vitamin B6 injection comprises the following specific steps:

[0038] (1) adding water-soluble fullerene to 25 wt% injection water and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding 45 wt% vitamin B6 nanocrystals, stirring (150 rpm) for 2 h, and obtaining a mixed solution a;

[0039] (2) adding the polyglutamic acid-polyethylene glycol complex to 25 wt% injection water and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding the remaining amount of vitamin B6 nanocrystals, stirring (150 rpm) for 2 h, and obtaining a mixed solution b;

[0040] (3) Mix the mixed solution a and the mixed solution b, make up the volume with the remaining amount of water for injection, add a pH adjuster to adjust the pH to 2.5±0.5, filter for the first time through a microporous membrane (pore size of 0.45 μm), add tetrahydromethylpyrimidine carboxylic acid, filter again through a microporous membrane (pore size of 0.21 μm), sterilize, and fill to obtain vitamin B6 injection.

[0041] Example 2

[0042] A vitamin B6 injection comprises the following raw materials in parts by weight: 10 parts of vitamin B6 nanocrystals, 0.5 parts of water-soluble fullerenes, 1 part of tetrahydromethylpyrimidine carboxylic acid, 0.8 parts of polyglutamic acid-polyethylene glycol complex, 1 part of pH regulator, and 100 parts of water for injection.

[0043] Preparation of vitamin B6 nanocrystals: Vitamin B6 was added to deionized water at a solid-liquid ratio of 1:10 mg / mL, ultrasonically treated at 50 rpm and 20°C for 5 min, frozen at -20°C, vacuum dried at 20 Pa for 8 h, and ground to obtain vitamin B6 nanocrystals with a particle size of 100 nm.

[0044] Preparation of polyglutamic acid-polyethylene glycol complex: polyglutamic acid and polyethylene glycol in a mass ratio of 1:1 are added to water (the amount of water added is 10 times the total mass of polyglutamic acid and polyethylene glycol), ultrasonically treated at 20 kHz and 30°C for 20 min, glutaraldehyde with a concentration of 0.1% w / v (glutaraldehyde to polyglutamic acid mass ratio of 0.1:1) is added, and the cross-linking reaction is continued at 30°C for 2 h. The mixture is centrifuged, washed and dried to obtain a polyglutamic acid-polyethylene glycol complex with a particle size of 200 nm.

[0045] The preparation method of the above vitamin B6 injection comprises the following specific steps:

[0046] (1) adding water-soluble fullerene to 20 wt% injection water and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding 40 wt% vitamin B6 nanocrystals, stirring (100 rpm) for 1 h, and obtaining a mixed solution a;

[0047] (2) adding the polyglutamic acid-polyethylene glycol complex to 20 wt% injection water and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding the remaining amount of vitamin B6 nanocrystals, stirring (100 rpm) for 1 hour, and obtaining a mixed solution b;

[0048] (3) Mix the mixed solution a and the mixed solution b, make up the volume with the remaining amount of water for injection, add a pH adjuster to adjust the pH to 2.5±0.5, filter for the first time through a microporous membrane (pore size of 0.4 μm), add tetrahydromethylpyrimidine carboxylic acid, filter again through a microporous membrane (pore size of 0.20 μm), sterilize, and fill to obtain vitamin B6 injection.

[0049] Example 3

[0050] A vitamin B6 injection comprises the following raw materials in parts by weight: 15 parts of vitamin B6 nanocrystals, 0.8 parts of water-soluble fullerenes, 2 parts of tetrahydromethylpyrimidine carboxylic acid, 1 part of polyglutamic acid-polyethylene glycol complex, 3 parts of pH regulators, and 200 parts of water for injection.

[0051] Preparation of vitamin B6 nanocrystals: Vitamin B6 was added to deionized water at a solid-liquid ratio of 1:20 mg / mL, ultrasonically treated at 100 rpm and 25°C for 10 min, frozen at -10°C, vacuum dried at 50 Pa for 12 h, and ground to obtain vitamin B6 nanocrystals with a particle size of 150 nm.

[0052] Preparation of polyglutamic acid-polyethylene glycol complex: polyglutamic acid and polyethylene glycol in a mass ratio of 1:5 are added to water (the amount of water added is 15 times the total mass of polyglutamic acid and polyethylene glycol), ultrasonically treated at 30kHz and 40°C for 30min, glutaraldehyde at a concentration of 0.3% w / v (glutaraldehyde to polyglutamic acid mass ratio 0.3:1) is added, and the cross-linking reaction is continued at 40°C for 4h, centrifuged, washed and dried to obtain a polyglutamic acid-polyethylene glycol complex with a particle size of 300nm.

[0053] The preparation method of the above vitamin B6 injection comprises the following specific steps:

[0054] (1) adding water-soluble fullerene to 30 wt% injection water and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding 50 wt% vitamin B6 nanocrystals, stirring (200 rpm) for 3 h, and obtaining a mixed solution a;

[0055] (2) adding the polyglutamic acid-polyethylene glycol complex to 30 wt% injection water and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding the remaining amount of vitamin B6 nanocrystals, stirring (200 rpm) for 3 h, and obtaining a mixed solution b;

[0056] (3) Mix the mixed solution a and the mixed solution b, make up the volume with the remaining amount of water for injection, add a pH adjuster to adjust the pH to 2.5±0.5, filter for the first time through a microporous membrane (pore size of 0.5 μm), add tetrahydromethylpyrimidine carboxylic acid, filter again through a microporous membrane (pore size of 0.22 μm), sterilize, and fill to obtain vitamin B6 injection.

[0057] Comparative Example 1

[0058] The difference from Example 1 is that vitamin B6 nanocrystals are replaced by vitamin B6, and the rest is the same as Example 1.

[0059] Comparative Example 2

[0060] The difference from Example 1 is that water-soluble fullerene is missing, and the rest is the same as Example 1.

[0061] Comparative Example 3

[0062] The difference from Example 1 is that ectoine is missing, and the rest is the same as Example 1.

[0063] Comparative Example 4

[0064] The difference from Example 1 is that the polyglutamic acid-polyethylene glycol complex is missing, and the rest is the same as Example 1.

[0065] Comparative Example 5

[0066] The difference from Example 1 is that the preparation process is different, and the rest is consistent with Example 1.

[0067] The preparation method of the vitamin B6 injection of the comparative example comprises the following specific steps: adding water-soluble fullerene and polyglutamic acid-polyethylene glycol complex to 25wt% injection water, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding vitamin B6 nanocrystals, stirring (150rpm) for 2h to obtain a mixed solution, adjusting the volume with the remainder of injection water, adding a pH adjuster to adjust the pH to 2.5±0.5, filtering through a microporous membrane (pore size of 0.45μm) for the first time, adding tetrahydromethylpyrimidine carboxylic acid, filtering through a microporous membrane (pore size of 0.21μm) again, sterilizing, and filling to obtain the vitamin B6 injection.

[0068] Test example

[0069] 1. The properties, pH, vitamin B6 content and impurity content of the vitamin B6 injection prepared in Examples 1-3 and Comparative Examples 1-5 were investigated, with the reference preparation as the control group. The results are shown in Table 1.

[0070] The information of the reference preparation is as follows:

[0071] name <![CDATA[Vitamin B6 Injection]]> Molecular formula <h2 style=";text-align:left;direction:ltr"><![CDATA[C8H <h2 style=";text-align:left;direction:ltr"> 11 <h2 style=";text-align:left;direction:ltr"> NO3·HCI]]><h2 style=";text-align:left;direction:ltr"> Molecular weight 205.64 Appearance Light yellow clear liquid Product Name Pyridoxine Hydrochloride Licensee FRESENIUS KABI USA LLC Specification 1ml:100mg

[0072] Table 1

[0073]

[0074]

[0075] 2. Stability under illumination and accelerated conditions: The vitamin B6 injections prepared in Examples 1-3 and Comparative Examples 1-5 were subjected to illumination for 10 days (storage conditions: 4500±500lx) and accelerated stability tests for 6 months (storage conditions: 50°C, 75%RH), and then compared with those at 0 day in terms of properties, pH, vitamin B6 content, and impurity content. The results are shown in Table 2.

[0076] Table 2

[0077]

[0078]

[0079] As can be seen from Table 2, compared with Comparative Examples 1-5, the vitamin B6 injections prepared in Examples 1-3 of the present invention have excellent stability under light and accelerated conditions, and their properties, pH, vitamin B6 content, single impurities and total impurities have no significant changes.

[0080] 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 vitamin B6 injection, characterized in that: The preparation comprises the following raw materials in parts by weight: 10-15 parts of vitamin B6 nanocrystals, 0.5-0.8 parts of water-soluble fullerenes, 1-2 parts of tetrahydromethylpyrimidine carboxylic acid, 0.8-1 parts of polyglutamic acid-polyethylene glycol complex, 1-3 parts of pH regulator, and 100-200 parts of water for injection.

2. A vitamin B6 injection as claimed in claim 1, characterized in that: The particle size of the vitamin B6 nanocrystals is 100-150nm.

3. A vitamin B6 injection as claimed in claim 1, characterized in that: The particle size of the polyglutamic acid-polyethylene glycol complex is 200-300 nm.

4. A vitamin B6 injection as claimed in claim 1, characterized in that: The method for preparing the vitamin B6 nanocrystals comprises: adding vitamin B6 into deionized water, ultrasonic treatment, freezing, vacuum drying, and grinding to obtain the vitamin B6 nanocrystals.

5. A vitamin B6 injection as claimed in claim 4, characterized in that: The solid-liquid ratio of vitamin B6 to ionized water is 1:10-20 mg / mL; the ultrasonic treatment is performed at 50-100 rpm and 20-25° C. for 5-10 min; the freezing temperature is minus 20° C. to minus 10° C.; the vacuum drying pressure is 20-50 Pa, and the time is 8-12 h.

6. A vitamin B6 injection as claimed in claim 1, characterized in that: The preparation method of the polyglutamic acid-polyethylene glycol complex comprises: adding polyglutamic acid and polyethylene glycol into water, ultrasonic treatment, adding glutaraldehyde for cross-linking reaction, centrifugation, washing and drying to obtain the polyglutamic acid-polyethylene glycol complex.

7. A vitamin B6 injection as claimed in claim 6, characterized in that: The mass ratio of polyglutamic acid to polyethylene glycol is 1:1-5; the amount of water added is 10-15 times the total mass of polyglutamic acid and polyethylene glycol; the ultrasonic treatment is carried out at 20-30kHz, 30-40°C for 20-30min; the concentration of glutaraldehyde is 0.1%-0.3% w / v; the mass ratio of polyglutamic acid to glutaraldehyde is 1:0.1-0.3; and the cross-linking reaction is carried out at 30-40°C for 2-4h.

8. The method for preparing a vitamin B6 injection according to claim 1, characterized in that: The specific steps include: (1) adding water-soluble fullerene to injection water in a formula amount of 20-30 wt% and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding vitamin B6 nanocrystals in a formula amount of 40-50 wt%, stirring evenly, and obtaining a mixed solution a; (2) adding the polyglutamic acid-polyethylene glycol complex to 20-30 wt% injection water and mixing evenly, adding medicinal charcoal, stirring for adsorption, decarbonizing and filtering, adding the remaining amount of vitamin B6 nanocrystals, stirring evenly, and obtaining a mixed solution b; (3) Mix the mixed solution a and the mixed solution b, add the remaining amount of water for injection to make up the volume, add a pH adjuster to adjust the pH to 2-3, filter through a microporous membrane for the first time, add tetrahydromethylpyrimidine carboxylic acid, filter through a microporous membrane again, sterilize, and fill to obtain a vitamin B6 injection solution.

9. The method for preparing a vitamin B6 injection according to claim 8, characterized in that: In steps (1) and (2), the stirring speed is 100-200 rpm and the time is 1-3 h.

10. The method for preparing a vitamin B6 injection according to claim 8, characterized in that: In step (3), the pore size of the first microporous membrane filtration is 0.4-0.5 μm; the pore size of the second microporous membrane filtration is 0.20-0.22 μm.

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