Inosine injection and preparation method thereof

Abstract

The invention provides an inosine injection and a preparation method thereof, and relates to the technical field of injection preparation. The inosine injection is jointly prepared from inosine, NaOH, NaCl, phospholipid, tert-butyl p-hydroxyanisole and water for injection, the pH value of a system is adjusted to 8.7-8.8 through HCl, in the preparation process, the inosine and the phospholipid are pressurized and stirred at a high speed, then the inosine and the phospholipid and a NaOH solution in which the tert-butyl p-hydroxyanisole is dissolved are dropwise added and stirred at a high speed, and then other raw materials are mixed. The invention overcomes the defects of the prior art, effectively enhances the oxidation resistance of the inosine injection, further enhances the storage stability of the inosine injection in various environments, ensures the use safety of the injection, and reduces the waste.

Description

Technical Field

[0001] The invention relates to the technical field of injection preparation, and in particular to an inosine injection and a preparation method thereof. Background Art

[0002] Inosine is a hypoxanthine nucleoside, a component of ATP, coenzyme A, ribonucleic acid and deoxyribonucleic acid in the body, and participates in the body's material metabolism and energy metabolism. It can increase the body's ATP level, can be converted into a variety of nucleotides, and participate in protein synthesis. Inosine has good permeability to cell membranes, can directly enter cells, convert into nucleotides, and further become ATP to participate in metabolism, which can promote liver cell recovery and prevent fatty liver. It can also increase the activity of various enzymes and stimulate the body to produce antibodies.

[0003] In addition, inosine can be used as an injection. Inosine injection is an auxiliary drug, mainly used for patients with thrombocytopenia or leukocytopenia, patients with various acute and chronic liver diseases, patients with cor pulmonale and central retinitis, etc. It cannot treat the primary disease, but can relieve the symptoms.

[0004] Generally, inosine injection is a colorless or almost colorless clear liquid. However, existing inosine injection is prone to oxidation and deterioration during production, storage and transportation, which seriously affects the effect and safety of the injection. Therefore, it is objectively important to improve the antioxidant property and stability of inosine injection in view of this phenomenon. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides an inosine injection and a preparation method thereof, which effectively improves the antioxidant performance of the inosine injection and further improves its storage stability under various environments, thereby ensuring the safe use of the injection and reducing waste.

[0006] To achieve the above objectives, the technical solution of the present invention is implemented through the following technical solutions:

[0007] Disclosed is an inosine injection. Each 1000 mL of the inosine injection comprises 20-50 g of inosine, 5-12 g of NaOH, 8.8 g of NaCl, 0.8-1.2 g of phospholipids, 0.2-0.4 g of tert-butyl-p-hydroxyanisole, and the rest is injection water and HCl, wherein the amount of HCl is to adjust the pH value of the inosine injection to 8.7-8.8.

[0008] The preparation method comprises the following steps:

[0009] (1) Mix HCl and water for injection, dissolve them and obtain a dilute HCl solution for later use;

[0010] (2) dissolving NaOH in water for injection to prepare a NaOH solution with a pH value of 9.5-10 for later use;

[0011] (3) adding butylated p-hydroxyanisole to the NaOH solution and stirring to dissolve, to obtain a first mixed material for later use;

[0012] (4) After mixing inosine and phospholipids, add water for injection, increase the pressure and stir in an ice water bath to obtain a second mixed material for use;

[0013] (5) adding the first mixture dropwise to the second mixture in an ice water bath while stirring, and stirring and mixing after the addition is complete to obtain a third mixture for later use;

[0014] (6) Add NaCl to the third mixed material, stir in a water bath until evenly mixed, and then add water for injection to obtain a crude injection solution for later use;

[0015] (7) Add activated carbon to the crude injection solution, stir and filter it, adjust the pH of the filtrate to 8.7-8.8 with a dilute HCl solution, filter it, fill it with nitrogen and sterilize it to obtain inosine injection solution.

[0016] Preferably, in step (1), the mass ratio of HCl to water for injection is 1:1-2.

[0017] Preferably, the amount of water for injection added in step (4) is 3-5 times the total mass of inosine and phospholipids.

[0018] Preferably, the pressure of the boost stirring in step (4) is 1.2-2.4 MPa, the stirring speed is 1200-1600 r / min, and the stirring time is 20-30 min.

[0019] Preferably, the dripping speed in step (5) is 120-180 drops / min, and the rotation speed of the dripping and stirring is 400-600 r / min.

[0020] Preferably, in step (5), after the dropwise addition is complete, the speed of stirring and mixing is 1800-2000 r / min, and the stirring time is 20-40 min.

[0021] Preferably, in step (6), the water bath stirring temperature is 60-70° C., the stirring speed is 200-400 r / min, and the stirring time is 10-20 min.

[0022] Preferably, the amount of activated carbon added in step (7) is 0.1%-0.3% of the total mass of the crude injection solution, and the stirring speed is 400-600 r / min and the stirring time is 30-40 min.

[0023] Preferably, the fine filtration in step (7) is carried out by using a 0.22 μm filter element.

[0024] The present invention provides an inosine injection and a preparation method thereof, which has the following advantages over the prior art:

[0025] The present invention adds ingredients such as phospholipids and tert-butylated hydroxyanisole, which have good antioxidant effects. However, in the prior art, phospholipids and tert-butylated hydroxyanisole are used as additives for lipid injections, and inosine injection is an aqueous injection. Adding such substances may cause system instability. However, the present invention increases the pressure and stirs inosine and phospholipids at high speed, and then drips and stirs a NaOH solution in which tert-butylated hydroxyanisole is dissolved, so that the phospholipids and inosine form a stable microemulsion system, effectively ensures the antioxidant effect of the system, and improves the storage stability of the inosine injection. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0027] Embodiment 1:

[0028] Preparation of inosine injection (calculated based on 1000mL):

[0029] (1) Prepare the following materials: 20 g inosine, 5 g NaOH, 8.8 g NaCl, 0.8 g phospholipids, 0.2 g butylated p-hydroxyanisole, and prepare an excess of water for injection and a HCl solution prepared in a mass ratio of 1:1 between water for injection and HCl.

[0030] (2) Dissolve NaOH in water for injection to prepare a NaOH solution with a pH value of 9.5 for later use;

[0031] (3) adding butylated p-hydroxyanisole to the NaOH solution and stirring to dissolve, to obtain a first mixed material for later use;

[0032] (4) After mixing inosine and phospholipids, add injection water 3 times the total mass of the inosine and phospholipid mixture, increase the pressure to 1.2 MPa under ice water bath conditions, stir at 1600 r / min for 30 min, and obtain a second mixture for standby use;

[0033] (5) adding the first mixed material to the second mixed material at a dropping speed of 120 drops / min in an ice water bath environment, stirring at a speed of 400 r / min while adding, and stirring at a speed of 1800 r / min for 40 min after the dropping is complete, to obtain a third mixed material for standby use;

[0034] (6) Add NaCl to the third mixed material, adjust the rotation speed to 200 r / min at a water bath temperature of 60° C., stir for 20 min, and then add water for injection to 1000 mL to obtain a crude injection solution for standby use;

[0035] (7) Add activated carbon in an amount of 0.1% of the total mass of the crude injection solution, stir at 400 r / min for 40 min, and then filter coarsely. Use HCl solution to adjust the pH of the filtrate to 8.7, and then use a 0.22 μm filter element for fine filtration. Add water for injection again to 1000 mL, fill with nitrogen, and sterilize to obtain inosine injection solution.

[0036] Embodiment 2:

[0037] Preparation of inosine injection (calculated based on 1000mL):

[0038] (1) Prepare materials: 50 g inosine, 12 g NaOH, 8.8 g NaCl, 1.2 g phospholipids, 0.4 g butylated hydroxyanisole, and prepare excess water for injection and HCl solution prepared with a mass ratio of water for injection to HCl of 1:1;

[0039] (2) Dissolve NaOH in water for injection to prepare a NaOH solution with a pH value of 10 for later use;

[0040] (3) adding butylated p-hydroxyanisole to the NaOH solution and stirring to dissolve, to obtain a first mixed material for later use;

[0041] (4) After mixing inosine and phospholipids, add water for injection in an amount 3 times the total mass of the inosine and phospholipid mixture, increase the pressure to 1.6 MPa in an ice water bath, and stir at 1200 r / min for 20 min to obtain a second mixture for standby use;

[0042] (5) adding the first mixed material to the second mixed material at a dropping speed of 180 drops / min in an ice water bath environment, stirring at a speed of 600 r / min while dropping, and stirring at a speed of 2000 r / min for 20 min after the dropping is complete, to obtain a third mixed material for standby use;

[0043] (6) Add NaCl to the third mixed material, adjust the rotation speed to 400 r / min at a water bath temperature of 70° C., stir for 10 min, and then add water for injection to 1000 mL to obtain a crude injection solution for standby use;

[0044] (7) 0.2% of the total mass of the crude injection solution was added with activated carbon, and then the mixture was stirred at 400 r / min for 40 min and then coarsely filtered. The pH of the filtrate was adjusted to 8.8 with HCl solution, and then finely filtered with a 0.22 μm filter element. The injection water was added again to 1000 mL, and then nitrogen was filled and sterilized to obtain inosine injection solution.

[0045] Comparative Example 1:

[0046] Preparation of inosine injection (calculated based on 1000mL):

[0047] (1) Preparation: 50 g of inosine, 12 g of NaOH, 8.8 g of NaCl, excess water for injection, and HCl solution prepared with a mass ratio of water for injection to HCl of 1:1;

[0048] (2) Dissolve NaOH in water for injection to prepare a NaOH solution with a pH value of 10 for later use;

[0049] (3) dissolving inosine in the prepared NaOH solution to obtain a mixed solution for later use;

[0050] (4) Add NaCl to the mixed solution, adjust the speed to 400 r / min at a 70°C water bath temperature, stir for 10 min, and then add water for injection to 1000 mL to obtain a crude injection solution for use;

[0051] (5) Add activated carbon in an amount of 0.2% of the total mass of the crude injection solution, stir at 400 r / min for 40 min, and then filter coarsely. Use HCl solution to adjust the pH of the filtrate to 8.8, and then use a 0.22 μm filter element for fine filtration. Add water for injection again to 1000 mL, fill with nitrogen, and sterilize to obtain inosine injection solution.

[0052] Comparative Example 2:

[0053] Preparation of inosine injection (calculated based on 1000mL):

[0054] (1) Prepare materials: 50 g inosine, 12 g NaOH, 8.8 g NaCl, 0.4 g butylated p-hydroxyanisole, and prepare excess water for injection and HCl solution prepared with a mass ratio of water for injection to HCl of 1:1;

[0055] (2) Dissolve NaOH in water for injection to prepare a NaOH solution with a pH value of 10 for later use;

[0056] (3) adding butylated p-hydroxyanisole to the NaOH solution and stirring to dissolve, to obtain a first mixed material for later use;

[0057] (4) adding inosine to the first mixture and stirring at a speed of 2000 r / min for 20 min to obtain a second mixture for later use;

[0058] (5) Add NaCl to the second mixed material, adjust the rotation speed to 400 r / min at a water bath temperature of 70° C., stir for 10 min, and then add water for injection to 1000 mL to obtain a crude injection solution for standby use;

[0059] (6) Add activated carbon in an amount of 0.2% of the total mass of the crude injection solution, stir at 400 r / min for 40 min, and then filter coarsely. Use HCl solution to adjust the pH of the filtrate to 8.8, and then use a 0.22 μm filter element for fine filtration. Add water for injection again to 1000 mL, fill with nitrogen, and sterilize to obtain inosine injection solution.

[0060] Comparative Example 3:

[0061] Preparation of inosine injection (calculated based on 1000mL):

[0062] (1) Prepare materials: 50 g inosine, 12 g NaOH, 8.8 g NaCl, 1.2 g phospholipids, and prepare excess water for injection and HCl solution prepared with a mass ratio of water for injection to HCl of 1:1;

[0063] (2) Dissolve NaOH in water for injection to prepare a NaOH solution with a pH value of 10 for later use;

[0064] (3) After mixing inosine and phospholipids, add injection water 3 times the total mass of the inosine and phospholipid mixture, increase the pressure to 1.6 MPa under ice water bath conditions, stir at 1200 r / min for 20 min, and obtain a first mixture for standby use;

[0065] (4) In an ice water bath environment, the NaOH solution is added dropwise to the first mixed material at a dropping speed of 180 drops / min, and the mixture is stirred at a speed of 600 r / min while the addition is completed. After the addition is complete, the mixture is stirred at a speed of 2000 r / min for 20 min to obtain a second mixed material for standby use;

[0066] (5) Add NaCl to the second mixed material, adjust the rotation speed to 400 r / min at a water bath temperature of 70° C., stir for 10 min, and then add water for injection to 1000 mL to obtain a crude injection solution for standby use;

[0067] (6) Add activated carbon in an amount of 0.2% of the total mass of the crude injection solution, stir at 400 r / min for 40 min, and then filter coarsely. Use HCl solution to adjust the pH of the filtrate to 8.8, and then use a 0.22 μm filter element for fine filtration. Add water for injection again to 1000 mL, fill with nitrogen, and sterilize to obtain inosine injection solution.

[0068] Detection:

[0069] The content of inosine was tested according to the standard test method of the 2010 edition of the Chinese Pharmacopoeia:

[0070] Take inosine injection, add water for injection to make a solution containing 10 μg per 1 mL, and measure its absorbance at 248 nm by spectrophotometry. 10 H 12 The absorption coefficient of N4O5 is calculated at 460nm;

[0071] 1. Stability at room temperature:

[0072] Each group of inosine injection was filled into 2 mL ampoule bottles and placed at 25°C ± 2°C and relative humidity 60% ± 10%. The relative inosine content after 0 day, 1 month, 3 months and 9 months was tested. The specific results are shown in the following ratio 1 (the inosine content is based on the labeled amount as 100%):

[0073] Table 1

[0074]

[0075] 2. High temperature storage stability:

[0076] Each group of inosine injection was filled into 2 mL ampoule bottles and sterilized, and then placed in a stabilization box. The storage temperature was controlled at 60°C, and the inosine injections were placed for 0 days, 20 days, 40 days and 60 days. The changes in the relative inosine content of each group of inosine injections after placement were detected. The specific results are shown in Table 2 below (the inosine content is based on the labeled amount as 100%):

[0077] Table 2

[0078]

[0079] 3. Light placement stability

[0080] Each group of inosine injection was filled into a transparent vial and sterilized, and then placed in a stabilization box. The light intensity was adjusted to 4500±500lx, the temperature was 25±2°C, and the humidity was 50%±5%. The inosine injections were placed for 0d, 10d, 30d, and 60d. The changes in the relative inosine content of each group of inosine injections after placement were detected. The specific results are shown in Table 3 below (the inosine content is based on the labeled amount as 100%).

[0081] Table 3

[0082]

[0083] 4. Freeze-thaw stability:

[0084] Each group of inosine injection was filled into a 2 mL ampoule bottle and sterilized, and then placed in a freezer at -20°C for 2 hours, taken out and thawed in a 30°C water bath, and then restored to room temperature, completing one freeze-thaw cycle. The changes in the relative inosine content of each group of inosine injection after 0, 5, 10, and 20 freeze-thaw cycles were detected. The specific results are shown in Table 4 below (the inosine content is based on the labeled amount as 100%):

[0085] Table 4

[0086]

[0087] It can be seen from the above tests that the inosine injections prepared in Examples 1-2 all have good stability.

[0088] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An inosine injection, characterized in that: Each 1000 mL of the inosine injection contains 20-50 g of inosine, 5-12 g of NaOH, 8.8 g of NaCl, 0.8-1.2 g of phospholipids, 0.2-0.4 g of butylated p-hydroxyanisole, and the rest is injection water and HCl, and the amount of HCl is used to adjust the pH of the inosine injection to 8.7-8.

8.

2. A method for preparing the inosine injection according to claim 1, characterized in that: The preparation method comprises the following steps: (1) Mix HCl and water for injection, dissolve them and obtain a dilute HCl solution for later use; (2) dissolving NaOH in water for injection to prepare a NaOH solution with a pH value of 9.5-10 for later use; (3) adding butylated p-hydroxyanisole to the NaOH solution and stirring to dissolve, to obtain a first mixed material for later use; (4) After mixing inosine and phospholipids, add water for injection, increase the pressure and stir in an ice water bath to obtain a second mixed material for use; (5) adding the first mixture dropwise to the second mixture in an ice water bath while stirring, and stirring and mixing after the addition is complete to obtain a third mixture for later use; (6) Add NaCl to the third mixed material, stir in a water bath until evenly mixed, and then add water for injection to obtain a crude injection solution for later use; (7) Add activated carbon to the crude injection solution, stir and filter it, adjust the pH of the filtrate to 8.7-8.8 with a dilute HCl solution, filter it, fill it with nitrogen and sterilize it to obtain inosine injection solution.

3. The preparation method according to claim 2, characterized in that: In the step (1), the mass ratio of HCl to water for injection is 1:1-2.

4. The preparation method according to claim 2, characterized in that: The amount of water for injection added in step (4) is 3-5 times the total mass of inosine and phospholipids.

5. The preparation method according to claim 2, characterized in that: In the step (4), the pressure of the boost stirring is 1.2-2.4 MPa, the stirring speed is 1200-1600 r / min, and the stirring time is 20-30 min.

6. The preparation method according to claim 2, characterized in that: The dripping speed in step (5) is 120-180 drops / min, and the rotation speed of the dripping and stirring is 400-600 r / min.

7. The preparation method according to claim 2, characterized in that: After the dropwise addition in step (5) is complete, the speed of stirring and mixing is 1800-2000 r / min, and the stirring time is 20-40 min.

8. The preparation method according to claim 2, characterized in that: In the step (6), the water bath stirring temperature is 60-70° C., the stirring speed is 200-400 r / min, and the stirring time is 10-20 min.

9. The preparation method according to claim 2, characterized in that: In the step (7), the amount of activated carbon added is 0.1%-0.3% of the total mass of the crude injection solution, and the stirring speed is 400-600r / min, and the stirring time is 30-40min.

10. The preparation method according to claim 2, characterized in that: The fine filtration in step (7) is performed by using a 0.22 μm filter element.

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