Coenzyme Q10 injection and preparation method thereof

Abstract

The invention relates to a coenzyme Q10 injection and a preparation method thereof.The injection prescription contains coenzyme Q10, vitamin E and glycerin, sodium glycerophosphate, a phosphate buffer solution and sodium chloride can also be added in the prescription, and the preferable specification is 2 ml: 5 mg. The coenzyme Q10 injection prepared according to the prescription technology has the advantages of being high in safety of auxiliary materials, simple in technology, low in cost and the like. The pharmaceutical composition has the characteristics of extremely high quality stability, low content of insoluble particles, difficulty in crystallization and good safety, and is obviously superior to the prior art.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly relates to a coenzyme Q10 injection and a preparation method thereof. Background Art

[0002] Coenzyme Q10, with the chemical name 2-[(all-E)-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone, also known as "ubiquinone", is a fat-soluble natural vitamin-like substance that exists widely in various organisms and is a coenzyme for mitochondrial oxidative phosphorylation. Coenzyme Q10 is a multi-functional biochemical drug with natural antioxidant and cell metabolism activation effects, which can significantly improve human immunity. Clinically, this drug is mainly used for the treatment of cardiovascular diseases, scurvy, aplastic anemia, duodenal ulcer, acute and chronic viral hepatitis, subacute hepatic necrosis, congestive heart disease, emphysema, etc., as well as adjuvant treatment for cancer patients, showing broad clinical application prospects. Coenzyme Q10 is a yellow or orange-yellow crystalline powder, odorless and tasteless, easily soluble in chloroform, benzene, carbon tetrachloride, soluble in acetone, ether, slightly soluble in ethanol, and insoluble in water and methanol. There is a quinone group in its molecular structure, and it is easily decomposed by light and oxygen. These physical and chemical properties make it very difficult to prepare a long-term stable coenzyme Q10 injection. The currently marketed coenzyme Q10 products are mostly in the forms of tablets, capsules, soft capsules, etc. The common drawback of these dosage forms is the low bioavailability after oral administration. Preparing coenzyme Q10 into an injection and directly administering it intravenously can significantly improve the bioavailability of coenzyme Q10. However, due to the poor solubility of coenzyme Q10, solubilizers need to be added to improve solubility when preparing injection preparations according to the existing technology, such as polysorbate 80 (Tween 80), propylene glycol, PEG, etc. For example: In the "Coenzyme Q10 Injection" disclosed in Chinese Application No. 200610086747.9, the solubilizer is composed of polysorbate 80 (Tween 80) and polyoxyethylene fatty acid ester (polyoxyethylene fatty acid 40 ester) in a certain proportion; Chinese Application No. 200410022007.X mainly solubilizes coenzyme Q10 by adding a high concentration of surfactant polysorbate 80 (Tween 80), thus successfully preparing it into an injection and other technical solutions. These solutions all use a large proportion of the surfactant polysorbate 80 (Tween 80) to solubilize coenzyme Q10. Since polysorbate 80 (Tween 80) has great safety problems in clinical applications, especially in intravenous administration preparations, Chinese Application No. 202110705672.2 adopted a new formulation to avoid using polysorbate 80 (Tween 80), but this formulation contains hydroxypropyl betacyclodextrin, and the dosage is as high as 0.1 - 5%. Hydroxypropyl betacyclodextrin has a hemolytic risk, and the risk is even greater at such a high concentration; the above reflects that there is still a large room for optimization in the existing technology for the characteristics of coenzyme Q10. Summary of the Invention

[0003] The object of the present invention is to provide a coenzyme Q10 injection and its preparation method in view of the above technical problems. Compared with the prior art, this injection avoids the use of excipients with greater safety risks, has a simple preparation process, is not prone to crystallization, has stable quality indicators, low impurity content, is significantly superior to the prior art, and can significantly improve the safety problems in the use of coenzyme Q10 injection.

[0004] The solution adopted by the present invention to solve the above technical problems is as follows:

[0005] The coenzyme Q10 injection is composed of coenzyme Q10, excipients and water for injection.

[0006] Preferably, the excipients are vitamin E and glycerol.

[0007] Preferably, the excipients further include: sodium glycerophosphate and phosphate buffer solution.

[0008] Preferably, the concentration of coenzyme Q10 is: 0.25%; the concentration of vitamin E is: 0.35% - 0.45%, most preferably 0.4%; the concentration of glycerol is: 3.5% - 4.5%, most preferably 4.0%.

[0009] Preferably, the concentration of sodium glycerophosphate is 0.03% - 0.05%, most preferably 0.04%; the phosphate buffer solution is: pH 5.0 phosphate buffer solution (take a certain amount of 0.2 mol / L sodium dihydrogen phosphate solution, adjust the pH value to 5.0 with sodium hydroxide test solution, and you will get it), and the concentration is 8% - 12%, most preferably 10%.

[0010] Preferably, the specification of the coenzyme Q10 injection is 2 ml: 5 mg.

[0011] Preferably, in order to adjust the osmotic pressure of the coenzyme Q10 injection in any embodiment of the present invention, the excipients further include sodium chloride as an osmotic pressure regulator.

[0012] Preferably, the concentration of sodium chloride is 0.8%.

[0013] The present invention also provides a preparation method for the above coenzyme Q10 injection, including the following steps:

[0014] (1) Mix the prescribed amount of coenzyme Q10 and vitamin E, heat to a transparent liquid at 70°C, and slowly add the prescribed amount of glycerol under continuous stirring, and heat to a transparent state at 70°C to obtain the first liquid;

[0015] (2) Dissolve the prescribed amount of sodium chloride, sodium glycerophosphate, and phosphate buffer solution in water for injection respectively to obtain the second liquid;

[0016] (3) Add the second liquid to the first liquid, stir continuously at 70 °C until it becomes orange-yellow and transparent, add water for injection to the full volume, cool to about 30 °C, measure the pH value and content of the solution, filter with a microporous filter element, fill it into ampoules according to the specifications, and sterilize to obtain Coenzyme Q10 Injection.

[0017] Preferably, in step (2), the excipients are dissolved in 50% of the water for injection in the prescription amount.

[0018] Preferably, the microporous filter element is a 0.22 μm microporous filter element.

[0019] Preferably, the sterilization conditions are moist heat sterilization at 121 °C for 15 minutes.

[0020] The present invention uses glycerol and vitamin E as excipients for Coenzyme Q10 Injection, and unexpectedly finds that the combined use of these two excipients is beneficial to increasing the solubility of Coenzyme Q10 while ensuring that Coenzyme Q10 is not easily crystallized at low temperatures, and also has an unexpected effect on stabilizing impurities and insoluble particles after sterilization. Especially when the concentration of vitamin E is 0.4% and the concentration of glycerol is 4%, the effect of this specific ratio is the best.

[0021] Furthermore, adding sodium glycerophosphate and phosphate buffer in the prescription also achieves an unexpected technical effect on the stability of Coenzyme Q10. Detailed implementation mode

[0022] The present invention can be further described through the following examples, however, the scope of the present invention is not limited to the following examples.

[0023] Example 1 Coenzyme Q10 Injection (2ml: 5mg) was prepared by the following steps

[0024] (1) Mix the prescription amount of Coenzyme Q10 and vitamin E, heat to a transparent liquid at 70 °C, and slowly add the prescription amount of glycerol under continuous stirring, and heat to a transparent state at 70 °C to obtain the first liquid;

[0025] (2) Add water for injection to the first liquid, stir continuously at 70 °C until it becomes orange-yellow and transparent, add water for injection to the full volume, cool to about 30 °C, measure the pH value and content of the solution, filter with a 0.22 μm microporous filter element, fill it into ampoules according to the specifications, and sterilize at 121 °C for 15 minutes by moist heat to obtain Coenzyme Q10 Injection.

[0026] The specific prescription amounts are shown in Table 1:

[0027] Table 1 Different prescriptions

[0028]

[0029] The Coenzyme Q10 injection prepared from the above 7 prescriptions was subjected to stress testing. It was placed at 60°C and under strong light (4500 lx ± 500 lx) for 10 days. For the light test, the ampoules were directly placed under the light source without additional outer packaging. Samples were taken for inspection on the 10th day, and the results were compared with those on the 0th day to examine the stability of the samples. The results are shown in Table 2 - Table 3:

[0030] Table 2 Results of the stability test of insoluble particles at 60°C

[0031]

[0032] Table 3 Results of the stability test of insoluble particles under strong light (4500 lx ± 500 lx)

[0033]

[0034] Table 4 Results of the stability test of content and impurities at 60°C

[0035]

[0036] Table 5 Results of the stability test of content and impurities under strong light (4500 lx ± 500 lx)

[0037]

[0038] From the test results in Table 2 - Table 5, it can be seen that vitamin E and glycerol, as excipients for Coenzyme Q10 injection, are beneficial to increasing the stability of Coenzyme Q10 injection, maintaining a low number of insoluble particles, and having good stability. In particular, the best effect is achieved with a specific ratio of adding 4.0 g of vitamin E and 40 g of glycerol per 1000 ml. At the same time, the Coenzyme Q10 injection prepared from 7 prescriptions did not show crystallization after being placed at 4°C for 30 days.

[0039] However, due to the characteristic of the light instability of Coenzyme Q10 itself, its stability is poor under light conditions, especially the changes in content and total impurity content are huge. The inventors unexpectedly found that on the basis of existing vitamin E and glycerol as excipients, adding sodium glycerophosphate to the prescription can significantly improve the light stability of Coenzyme Q10 injection.

[0040] Example 2 The Coenzyme Q10 injection (2 ml: 5 mg) was prepared using the following steps

[0041] (1) Mix the prescribed amount of Coenzyme Q10 and vitamin E, heat to a transparent liquid at 70°C, and slowly add the prescribed amount of glycerol with continuous stirring, and heat to a transparent state at 70°C to obtain the first liquid;

[0042] (2) Dissolve the prescribed amount of sodium glycerophosphate in 50% of the injection water in the prescribed amount to obtain the second liquid;

[0043] (3) Add the second liquid to the first liquid, stir continuously at 70 °C until it becomes orange-yellow and transparent, add water for injection to the full volume, cool to about 30 °C, measure the pH value and content of the solution, filter with a 0.22 μm microporous filter element, fill into ampoules according to the specifications, and sterilize by moist heat at 121 °C for 15 minutes to obtain Coenzyme Q10 Injection.

[0044] The specific prescription amounts are shown in Table 6:

[0045] Table 6 Different Prescriptions

[0046]

[0047] Conduct the influencing factor test on the Coenzyme Q10 Injection prepared from the above 3 prescriptions. Place it under strong light (4500 lx ± 500 lx) for 10 days. For the light test, directly place the ampoules under the light source without adding outer packaging. Sample and inspect on the 10th day respectively. Compare the results with those on the 0th day to investigate the stability of the sample. The results are shown in Table 7:

[0048] Table 7 Test Results of Content and Impurity Stability under Strong Light (4500 lx ± 500 lx)

[0049]

[0050] It can be seen from the test results in Table 7 that vitamin E and glycerol, as excipients for Coenzyme Q10 Injection, and adding sodium glycerophosphate is beneficial to improving the light stability of Coenzyme Q10 Injection. Especially, the effect of adding 0.4 g per 1000 ml in a specific ratio is the best.

[0051] Example 3 Prepare Coenzyme Q10 Injection (2 ml: 5 mg) using the following steps

[0052] (1) Mix the prescription amount of Coenzyme Q10 and vitamin E, heat to a transparent liquid at 70 °C, and slowly add the prescription amount of glycerol under continuous stirring. Heat to a transparent state at 70 °C to obtain the first liquid;

[0053] (2) Dissolve the prescription amount of sodium glycerophosphate and pH 5.0 phosphate buffer in 50% of the water for injection in the prescription amount to obtain the second liquid;

[0054] (3) Add the second liquid to the first liquid, stir continuously at 70 °C until it becomes orange-yellow and transparent, add water for injection to the full volume, cool to about 30 °C, measure the pH value and content of the solution, filter with a 0.22 μm microporous filter element, fill into ampoules according to the specifications, and sterilize by moist heat at 121 °C for 15 minutes to obtain Coenzyme Q10 Injection.

[0055] The specific prescription amounts are shown in Table 8:

[0056] Table 8 Different prescriptions

[0057]

[0058] The coenzyme Q10 injections prepared by the above four prescriptions were examined for changes in pH before and after sterilization. The sterilization conditions were wet heat sterilization at 121°C for 15 minutes. The specific results are shown in Table 9:

[0059] Table 9 pH change results of different prescriptions

[0060]

[0061] It can be seen from the test results in Table 9 that vitamin E, glycerol, and sodium glycerophosphate as excipients of coenzyme Q10 injection and then adding pH 5.0 phosphate buffer are beneficial to increasing the pH stability of coenzyme Q10 injection before and after light sterilization. The stability of pH before and after sterilization is also important in maintaining the stability of coenzyme Q10 injection, especially the specific ratio of adding 100 ml to every 1000 ml has the best effect.

[0062] Example 4 The following steps are used to prepare coenzyme Q10 injection (2ml: 5mg)

[0063] (1) Mix 2.5 g of coenzyme Q10 and 4 g of vitamin E, heat at 70°C until a transparent liquid is formed, slowly add 40 g of glycerol while stirring continuously, and heat at 70°C until a transparent state is formed to obtain the first liquid;

[0064] (2) Add 0.4 g of sodium glycerophosphate and 100 ml of pH 5.0 phosphate buffer to 50% of the prescribed injection volume of water and dissolve to obtain the second solution;

[0065] (3) Add the second liquid to the first liquid, stir continuously at 70°C until it becomes orange-yellow and transparent, add water for injection to a total of 1000 ml, cool to about 30°C, measure the pH value and content of the solution, filter with a 0.22μm microporous filter, fill into ampoules according to specifications, and sterilize at 121°C for 15 minutes to obtain coenzyme Q10 injection.

[0066] Example 5 The following steps are used to prepare coenzyme Q10 injection (2ml: 5mg)

[0067] (1) Mix 2.5 g of coenzyme Q10 and 4 g of vitamin E, heat at 70°C until a transparent liquid is formed, slowly add 40 g of glycerol while stirring continuously, and heat at 70°C until a transparent state is formed to obtain the first liquid;

[0068] (2) Add 8 g of sodium chloride, 0.4 g of sodium glycerophosphate and 100 ml of pH 5.0 phosphate buffer to 50% of the prescribed amount of injection water and dissolve to obtain the second solution;

[0069] (3) Add the second liquid to the first liquid, stir continuously at 70°C until it becomes orange-yellow and transparent, add injection water to make up the total volume to 1000 ml, cool to about 30°C, measure the pH value and content of the solution, filter through a 0.22 μm microporous filter element, fill into ampoules according to the specifications, and sterilize by moist heat at 121°C for 15 minutes to obtain Coenzyme Q10 Injection.

[0070] Example 6 Coenzyme Q10 Injection (2 ml: 5 mg) was prepared by the following steps

[0071] (1) Heat 2.5 g of Coenzyme Q10 and 40 g of glycerol to 70°C until they are mixed evenly. Slowly add 4 g of vitamin E under continuous stirring, and heat and stir to mix at 70°C. It is impossible to make it transparent, and the first liquid is obtained.

[0072] (2) Dissolve 8 g of sodium chloride, 0.4 g of sodium glycerophosphate and 100 ml of pH 5.0 phosphate buffer solution in 50% of the injection water in the prescription amount to obtain the second liquid.

[0073] (3) Add the second liquid to the first liquid, stir continuously at 70°C, and it is impossible to make a clear liquid, and the preparation fails. It shows that changing the addition order of glycerol and vitamin E has a decisive influence on the preparation of Coenzyme Q10 Injection.

[0074] Example 7 Coenzyme Q10 Injection (2 ml: 5 mg) was prepared by the following steps

[0075] (1) Mix 2.5 g of Coenzyme Q10 and 4 g of vitamin E, heat to a transparent liquid at 70°C, slowly add 40 g of glycerol under continuous stirring, and heat to a transparent state at 70°C to obtain the first liquid.

[0076] (2) Dissolve 8 g of sodium chloride, 0.4 g of sodium glycerophosphate and 100 ml of pH 5.0 phosphate buffer solution in 50% of the injection water in the prescription amount to obtain the second liquid.

[0077] (3) Add the first liquid to the second liquid, stir continuously at 70°C, and it is impossible to make a clear liquid, and the preparation fails. It shows that changing the mixing method of the solution has a decisive influence on the preparation of Coenzyme Q10 Injection.

[0078] The present invention also provides the following test examples:

[0079] Sample 1: Coenzyme Q10 Injection prepared in Example 4 of this application.

[0080] Sample 2: Coenzyme Q10 Injection prepared in Example 5 of this application.

[0081] Sample 3: Marketed Coenzyme Q10 Injection.

[0082] Test Example 1: Investigation on Crystallization of Coenzyme Q10 Injection

[0083] Samples 1 and 2 were placed in an environment at 4°C for 30 days, and whether crystallization occurred in the samples was observed. The specific test results are shown in Table 10:

[0084] Table 10 Crystallization Test Results

[0085]

[0086] It can be seen from the test results in Table 10 that the coenzyme Q10 injection prepared by the present invention can remain non-crystalline in a low-temperature environment for a long time, and has significant advantages compared with the prior art.

[0087] Test Example 2: Quality Investigation on the Accelerated Test of Coenzyme Q10 Injection.

[0088] Samples 2 and 3 were subjected to an accelerated stability investigation (40°C ± 2°C, RH 75% ± 5%) for 6 months. The results are shown in Table 11:

[0089] Table 11 Accelerated Test Results of Coenzyme Q10 Injection

[0090]

[0091] It can be seen from the results in Table 11 that the coenzyme Q10 injection prepared by the prescription and process of the present invention maintains extremely high stability, and has significant advantages in terms of insoluble particles and related substances compared with the marketed products. The same test was also carried out in Example 4, and similar results were obtained.

[0092] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A coenzyme Q10 injection, characterized in that: it is composed of coenzyme Q10, vitamin E, glycerol and water for injection.

2. The coenzyme Q10 injection according to claim 1, characterized in that: the concentration of the coenzyme Q10 is: 0.25%, the concentration of vitamin E is: 0.35% - 0.45%, and the concentration of glycerol is: 3.5% - 4.5%.

3. The coenzyme Q10 injection according to claim 2, characterized in that: the concentration of the vitamin E is: 0.4%, and the concentration of glycerol is: 4.0%.

4. The coenzyme Q10 injection according to any one of claims 1 to 3, characterized in that: it further contains 0.03% - 0.05% of sodium glycerophosphate and 8% - 12% of pH 5.0 phosphate buffer solution.

5. The coenzyme Q10 injection according to claim 4, characterized in that: the concentration of the sodium glycerophosphate is: 0.04%, and the concentration of the pH 5.0 phosphate buffer solution is 10%.

6. The coenzyme Q10 injection according to claim 5, characterized in that: it further contains 0.8% of sodium chloride.

7. The coenzyme Q10 injection according to claim 6, characterized in that: the specification of the coenzyme Q10 injection is 2 ml: 5 mg.

8. The preparation method of the coenzyme Q10 injection according to any one of claims 1 to 7, characterized in that, it is prepared by the following method: (1) Mix the prescribed amounts of coenzyme Q10 and vitamin E, heat to a transparent liquid at 70°C, and slowly add the prescribed amount of glycerol with continuous stirring, and heat to a transparent state at 70°C to obtain the first liquid; (2) Dissolve the prescribed amounts of sodium chloride, sodium glycerophosphate, and phosphate buffer solution in water for injection respectively to obtain the second liquid; (3) Add the second liquid to the first liquid, continuously stir at 70°C until it becomes an orange-yellow transparent state, add water for injection to the full volume, cool to about 30°C, measure the pH value and content of the solution, filter with a microporous filter element, fill into ampoules according to the specification, and sterilize to obtain the coenzyme Q10 injection.

9. The preparation method of the coenzyme Q10 injection according to claim 8, characterized in that: in step (2), the amount of water for injection used is 50% of the full volume, and the microporous filter element in step (3) is a 0.22 μm microporous filter element.

10. The preparation method of the coenzyme Q10 injection according to claim 8, characterized in that: the sterilization condition is moist heat sterilization at 121°C for 15 minutes.

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