Coenzyme q10 injection and preparation method

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a coenzyme Q10 injection and a preparation method thereof, which is composed of the following components by weight: 50 parts of coenzyme Q10, 400-80 parts of a solubilizing agent, 10-15 parts of an antioxidant vitamin E, 1-2 parts of an acidity regulator lactic acid, a pH regulator, and 15000-25000 parts of water for injection; the preparation method of the coenzyme Q10 injection comprises the following steps: dissolving the coenzyme Q10 in a mixed solution of the solubilizing agent and the antioxidant, adding the water for injection, heating and stirring, cooling to room temperature, adding the acidity regulator and the pH regulator in sequence, adjusting the pH to 3.2-5.5, supplementing the water for injection, filtering, filling and sealing, sterilizing, and obtaining the coenzyme Q10 injection; and the application can effectively improve the stability of the coenzyme Q10 injection and reduce the impurity content.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a coenzyme Q10 injection and its preparation method. Background Technology

[0002] Coenzyme Q10, chemically known as 2-[(per-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone, activates cell metabolism and is also a natural, fat-soluble antioxidant. Its structure is similar to vitamin E, vitamin K, and plastoquinone. In the human body, it mainly participates in intracellular energy activation and production, effectively preventing atherosclerosis. Furthermore, coenzyme Q10 promotes oxidative phosphorylation, effectively protecting the integrity of biological membranes, enhancing the body's immune function, activating human cells and cellular energy, and enhancing antioxidant, anti-aging, and vitality functions. Clinically, coenzyme Q10 injections are mainly used as adjunctive therapy for cardiovascular diseases, duodenal ulcers, and cancer patients, and are also widely used in food additives and nutritional supplements.

[0003] Coenzyme Q10 raw material is a yellow to orange-yellow crystalline powder, odorless and tasteless, insoluble in water and methanol, very slightly soluble in ethanol, soluble in ether and acetone, and readily soluble in chloroform, carbon tetrachloride, and benzene. Its molecular structure contains a quinone group, making it prone to decomposition upon exposure to light and oxygen, resulting in poor stability in formulations. Coenzyme Q10 dosage forms developed domestically and internationally include tablets, lyophilized formulations, and injections. Because coenzyme Q10 is classified as a Class II poorly soluble drug in the biopharmaceutical classification system, its low solubility and poor stability significantly increase the difficulty of its formulation preparation. In the preparation of coenzyme Q10 injections, some solubilizing excipients are added, such as polysorbate 80(II), a commonly used clinical solubilizer.

[0004] CN106491520A discloses a coenzyme Q10 injection preparation and its preparation method. The preparation method involves combining the active ingredient coenzyme Q10 with solubilizers, antioxidants, osmotic pressure regulators, etc. The active ingredient and solubilizer are dissolved by heating to achieve the effect of preparing an injection. However, the preparation process involves a large amount of excipients and the use of activated carbon for sterilization, which poses certain risks. In addition, the patent document does not provide data on low-temperature cycling and freeze-thaw cycling, making it impossible to ensure the stability of the coenzyme Q10 injection at low temperatures.

[0005] CN1823748A discloses a method for preparing coenzyme Q10 liposomes. The preparation consists of coenzyme Q10, lipid components, and pharmaceutical excipients. The method involves extruding a coenzyme Q10 suspension through a 0.2 μm filter membrane to form coenzyme Q10 liposomes. However, this liquid preparation requires lyophilization to maintain long-term stability.

[0006] CN115969782A discloses a coenzyme Q10 injection and its preparation method. The main active ingredient of the injection is coenzyme Q10. The method involves dissolving a solubilizer and antioxidant by heating in a water bath, adding an osmotic pressure regulator and preservative, and then adding water for injection to bring the volume to the mark and stirring to dissolve. This effectively solves the problem of coenzyme Q10's insolubility in water and reduces the impact of external factors such as temperature, oxygen, and light on the stability of the preparation, thus improving the safety and efficacy of the drug. However, no experimental data on stability are provided, and the stability of the sample under high temperature and light conditions cannot be clearly determined. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a coenzyme Q10 injection solution and a preparation method thereof, thereby improving the stability of the coenzyme Q10 injection solution and reducing the impurity content.

[0008] This invention provides a coenzyme Q10 injection solution, which is composed of the following components in parts by weight: 50 parts coenzyme Q10, 400-800 parts solubilizer, 10-15 parts antioxidant vitamin E, 1-2 parts acidity regulator lactic acid, pH adjuster (the amount of pH adjuster is controlled to make the pH 3.2-5.5), and 15,000-25,000 parts water for injection;

[0009] The preparation method of the coenzyme Q10 injection solution is as follows: dissolve coenzyme Q10 in a mixed solution of solubilizer and antioxidant, add water for injection, heat and stir, cool to room temperature, add acidity regulator and pH regulator successively to adjust the pH to 3.2-5.5, add water for injection, filter, fill and sterilize to obtain coenzyme Q10 injection solution.

[0010] Preferably, it is composed of the following components in parts by weight: 50 parts coenzyme Q10, 800 parts solubilizer, 10-15 parts antioxidant vitamin E, 1-2 parts acidity regulator lactic acid, pH adjuster and 20,000 parts water for injection.

[0011] Preferably, the solubilizer is a mixture of propylene glycol and polyoxyethylene 35 castor oil, or polysorbate 80II.

[0012] Preferably, the weight ratio of propylene glycol to polyoxyethylene 35 castor oil is 80:18, and the weight ratio of coenzyme Q10 to polyoxyethylene 35 castor oil is 5:18.

[0013] Preferably, the pH adjuster is sodium hydroxide.

[0014] Preferably, it also includes 150-300 parts of an osmotic pressure regulator, more preferably 200 parts, and the osmotic pressure regulator is preferably sodium chloride.

[0015] Preferably, the residual oxygen after filling is controlled to be no more than 1%, and the dissolved oxygen content of the coenzyme Q10 injection is controlled to be less than 1 mg / L.

[0016] This invention provides a method for preparing the coenzyme Q10 injection solution, comprising the following steps: dissolving coenzyme Q10 in a mixed solution of solubilizer and antioxidant, adding water for injection, heating and stirring, cooling to room temperature, adding an acidity regulator and a pH regulator to adjust the pH to 3.2-5.5, adding water for injection, filtering, filling, and sterilizing to obtain the coenzyme Q10 injection solution.

[0017] Preferably, the heating and stirring temperature is 50–70°C.

[0018] Preferably, during the filling process, nitrogen gas is purged before and after filling the drug solution to control the residual oxygen of the sample after filling to not exceed 1%; the filtration method is to pass the sample through microporous membranes of 0.45μm and 0.22μm in sequence.

[0019] The beneficial effects of this invention are:

[0020] (1) The coenzyme Q10 injection of the present invention can solve the problem of crystallization of this product.

[0021] (2) Adding an acidity regulator to the prescription and then adding a pH regulator can not only better regulate the pH value, but also significantly reduce the pH value change of the injection solution before and after sterilization and during the stability test.

[0022] (3) Heating the solubilizer before adding the active ingredient can improve the solubility of the active ingredient, effectively improve the mixing properties of the formulation, and enhance the stability of the formulation.

[0023] (4) Antioxidants have been added to this application, which can effectively improve the stability of the product.

[0024] (5) Nitrogen gas is used during the filling process, which can effectively reduce the residual oxygen content in the sample after filling and slow down the growth trend of impurities during sample placement, thereby improving the safety of the product.

[0025] (6) The inert gas is used for protection during the preparation process, which can effectively reduce the dissolved oxygen in the solution. The inert gas is used before and after filling, which can effectively reduce the oxygen in the ampoule and reduce the residual oxygen in the ampoule after filling, which is beneficial to reduce the impurity content in the finished product. Detailed Implementation

[0026] Experimental Example 1

[0027] Prescription composition screening

[0028] I. Investigation on the amount of solubilizing polyoxyethylene (35) castor oil used, as shown in Table 1.

[0029] Table 1. Investigation of Castor Oil Dosage for Solventizing Polyoxyethylene (35)

[0030]

[0031] Preparation process:

[0032] (1) Mix propylene glycol and polyoxyethylene (35) castor oil in a 65°C water bath for 30 min; then dissolve coenzyme Q10 in the mixture and heat and stir until homogeneous.

[0033] (2) Add 65℃ water for injection (80% of the total amount of water for injection and solubilizer) to the solution and stir at 65℃ for 10 min to mix evenly;

[0034] (3) Cool the solution to room temperature and stir to determine the pH value. Add sodium metabisulfite and stir for 10 min. Measure the pH value.

[0035] (4) Add an appropriate amount of acidity regulator lactic acid to adjust the pH value to 3.5-4.0, and filter with a 0.22μm PES filter membrane;

[0036] (5) Filling;

[0037] (6) Sterilization.

[0038] Experiment Example 2

[0039] II. The dosage of the solubilizer polysorbate 80(II) was investigated, as shown in Table 2.

[0040] Table 2. Analysis of the dosage of polysorbate 80(II) solubilizer

[0041] Prescription composition Coenzyme Q10 Polysorbate 80(II) Sodium metabisulfite Water for Injection Example 8 5mg 8mg 1.5mg 2ml Example 9 5mg 15mg 1.5mg 2ml Example 10 5mg 20mg 1.5mg 2ml Example 11 5mg 40mg 1.5mg 2ml Example 12 5mg 60mg 1.5mg 2ml Example 13 5mg 80mg 1.5mg 2ml Example 14 5mg 120mg 1.5mg 2ml Example 15 5mg 150mg 1.5mg 2ml

[0042] Preparation process:

[0043] (1) Mix polysorbate 80(II) and coenzyme Q10 in a 65℃ water bath for 30 minutes until they are evenly mixed;

[0044] (2) Add 65℃ water for injection (80% of the total amount of water for injection and solubilizer) to the solution and stir at 65℃ for 10 min to mix evenly;

[0045] (3) Cool the solution to room temperature and stir to determine the pH. Add the antioxidant sodium metabisulfite and stir for 10 min. Then determine the pH value.

[0046] (4) Add an appropriate amount of lactic acid to adjust the pH value to 3.5-4.0, and filter with a 0.22μm PES filter membrane;

[0047] (5) Filling;

[0048] (6) Sterilization.

[0049] The clarification of the drug solution in Examples 8-15 was tested, and the results are shown in Table 3.

[0050] Table 3. Clarification Performance of Drug Solution

[0051] Prescription composition The appearance of the sterilized solution (batch size approximately 100 vials). Example 8 14 samples did not clarify after shaking, but all clarified after standing for 12 hours. Example 9 Five samples did not clarify after shaking, but all clarified after standing for 12 hours. Example 10 One sample did not clarify after shaking, but all samples clarified after standing for 12 hours. Example 11 Clarification after shaking Example 12 Clarification after shaking Example 13 Clarification after shaking Example 14 Nine bottles did not clarify after shaking, but all clarified after standing for 12 hours. Example 15 Fifteen bottles did not clarify after shaking, but all clarified after standing for 12 hours.

[0052] This invention investigates in detail the types and amounts of solubilizers used in injection solutions. When using propylene glycol and polyoxyethylene (35) castor oil as solubilizers, the amount of propylene glycol is fixed, and the effects of different amounts of polyoxyethylene (35) castor oil on the clarification of the sterilized injection solution are investigated. The results show that the preferred weight ratio of coenzyme Q10 to polyoxyethylene (35) castor oil is 5:18.

[0053] Using polysorbate 80(II) as a solubilizer, the effects of different amounts of polysorbate 80(II) on the clarification of the sterilized injection solution were investigated. The results showed that the optimal weight ratio of coenzyme Q10 to polysorbate 80(II) was 5:40 to 5:80. Both excessively high and excessively low weight ratios of the active pharmaceutical ingredient and excipients had a certain impact on the solubility of coenzyme Q10.

[0054] Experimental Example 3

[0055] III. Examination of the order of addition of antioxidants. The formulations of Examples 16-17 are shown in Table 4 below.

[0056] Table 4. Examination of the order of addition of antioxidants

[0057] Prescription composition Example 16 Example 17 Coenzyme Q10 5mg 5mg Propylene glycol 80mg 80mg Polyoxyethylene (35) castor oil 18mg 18mg Sodium metabisulfite 2mg 2mg

[0058] Preparation process:

[0059] The preparation process of Example 16 is the same as that of Experimental Example 1;

[0060] The preparation process of Example 17 is as follows:

[0061] (1) Mix propylene glycol, polyoxyethylene (35) castor oil, coenzyme Q10 and antioxidant sodium metabisulfite in a 65°C water bath for 30 minutes until the mixture is homogeneous.

[0062] (2) Add 65℃ water for injection (80% total amount of water for injection + solubilizer) to the solution and stir at 65℃ for 10 min to mix evenly, and measure the pH value.

[0063] (3) Add an appropriate amount of lactic acid to adjust the pH value to 3.5-4.0, and filter with a 0.22μm PES filter membrane;

[0064] (4) Filling;

[0065] (5) Sterilization.

[0066] The clarification of the drug solutions in Examples 16-17 was tested, and the drug solutions in Examples 16-17 were all clear after preparation.

[0067] The results of the finished product inspection, including the order of addition of antioxidants, are shown in Table 5.

[0068] Table 5 Performance test results of Examples 16-17

[0069]

[0070] This invention examines the order of adding antioxidants. From the perspective of solution preparation time, adding solubilizer, antioxidant, and API simultaneously with stirring reduces the transfer of excipients during solution preparation and significantly shortens the preparation time. From the perspective of formulation content and related substances results, the samples prepared by adding solubilizer, antioxidant, and API simultaneously with stirring showed lower maximum single impurity and total impurity content in related substances tests compared to formulations where antioxidants were added at different steps. Therefore, it is preferable to add antioxidant, solubilizer, and API simultaneously with stirring and mixing until homogeneous.

[0071] Experiment Example 4

[0072] IV. Investigation of the types of antioxidants: The formulations of Examples 18-21 are shown in Table 6.

[0073] Table 6 Formulation table for Examples 18-21

[0074] Prescription composition Example 18 Example 19 Example 20 Example 21 Coenzyme Q10 5mg 5mg 5mg 5mg Propylene glycol 80mg 80mg 80mg 80mg Polyoxyethylene (35) castor oil 18mg 18mg 18mg 18mg Sodium metabisulfite 2mg / / / Thiourea / 2mg / / Vitamin E / / 2mg / Vitamin C / / / 2mg

[0075] The preparation processes for Examples 18-21 are as follows:

[0076] (1) Mix propylene glycol, polyoxyethylene (35) castor oil and antioxidant in a 65°C water bath for 30 minutes until the mixture is homogeneous; then dissolve coenzyme Q10 in the mixture and heat and stir until homogeneous.

[0077] (2) Add 65℃ water for injection (80% of the total amount of water for injection and solubilizer) to the solution and stir at 65℃ for 10 min to mix evenly;

[0078] (3) Cool the solution to room temperature by stirring, and then measure the pH.

[0079] (4) In Example 20, the prepared weak acid lactic acid was added, stirred for 15 minutes, and the pH value was measured. Then, sodium hydroxide was added to adjust the pH value of the solution to 3.5-4.0 and the volume was adjusted.

[0080] (5) Filling;

[0081] (6) Sterilization.

[0082] The results of the antioxidant type investigation - high temperature 60℃ stability are shown in Table 7.

[0083] Table 7 Results of the Investigation on Antioxidant Types

[0084]

[0085] This invention screens different antioxidants. Based on the content of the formulation and the results of related substances, vitamin E has a better antioxidant effect than other antioxidants. Therefore, vitamin E is temporarily selected as the antioxidant.

[0086] Experimental Example 5

[0087] Different acids were investigated as pH adjusters.

[0088] The use of different acids as pH adjusters in the formulation can have a significant impact on the pH value and related substances of the sample. This study investigates the effect of different acids on the stability of the formulation.

[0089] The preparation process of Examples 22-23 is the same as that of Examples 19-21, and the formula is shown in Table 8.

[0090] Table 8. Different Acid Formulations

[0091] batch number Example 22 Example 23 <![CDATA[Coenzyme Q 10 > 5mg 5mg Propylene glycol 80mg 80mg Polyoxyethylene (35) castor oil 18mg 18mg Vitamin E 1mg 1mg weak acid 0.2mg / HCl / Appropriate amount NaOH Appropriate amount / Water for Injection 2ml 2ml

[0092] The results of different acid tests at high temperature (60℃) are shown in Table 9.

[0093] Table 9 Results of the study on different acids

[0094]

[0095]

[0096] The results showed that when hydrochloric acid was used as a pH adjuster, the pH of the prepared solution ranged from 3.2 to 5.5, and the pH increased significantly after sterilization, exhibiting large pH variations during the influencing factors experiment. When lactic acid was used as a pH adjuster, the pH of the prepared solution was 4.0 before sterilization, and the pH changed to 4.3 after sterilization. When HCl was used as a pH adjuster, the pH of the prepared solution was 4.0 before sterilization, and the pH changed to 4.8 after sterilization. During the influencing factors experiment, the pH changes were smaller than those with hydrochloric acid. Therefore, lactic acid was used as the pH adjuster, followed by alkali adjustment to form a buffer system, which effectively reduced the pH fluctuations of the samples before and after sterilization, as well as during stability testing.

[0097] Experimental Example 6

[0098] According to the final formulation, the present invention prepared the drug solution by filling it with nitrogen gas for different times after weighing, based on the formulation and preparation process of Example 22, so that the dissolved oxygen of the drug solution is controlled in different ranges. Specifically, Example 24 has a dissolved oxygen control of <1 mg / L, Example 25 has a dissolved oxygen range of 1 mg / L to 2 mg / L, Example 26 has a dissolved oxygen range of 2 mg / L to 3 mg / L, and Example 27 has a dissolved oxygen >3 mg / L.

[0099] The results of the influencing factors of different dissolved oxygen levels are shown in Table 10.

[0100] Table 10 Results of factors affecting different dissolved oxygen levels

[0101]

[0102] The results showed that as the dissolved oxygen in the drug solution decreased, the increase in related substances during the influencing factor experiment showed a decreasing trend. The stability of the formulation with dissolved oxygen controlled at 1-2 mg / L and 2-3 mg / L was similar to that of the formulation with dissolved oxygen controlled at 2-3 mg / L. The increase in impurity content and impurities was significantly lower than that of the sample with dissolved oxygen >3 mg / L. However, when the dissolved oxygen was further reduced to below 1 mg / L, the increase in impurity content and impurities was even lower during the influencing factor experiment. Therefore, the dissolved oxygen was selected to be controlled below 1 mg / L.

[0103] According to the final formulation, this invention, based on the formulation and preparation process of Example 22, purged the filling solution with nitrogen for different times before and after filling to control the headspace residual oxygen of the filled product at different levels. Example 28 had a headspace residual oxygen control of <1%, Example 29 had a headspace residual oxygen control of 1%–2%, Example 30 had a headspace residual oxygen control of 2%–3%, and Example 31 had a headspace residual oxygen control of >3%. Stability tests were conducted on these three batches of samples, and the experimental data are shown in Table 11 below.

[0104] Table 11 Detection results of different residual oxygen levels

[0105]

[0106] The results showed that as the headspace residual oxygen of the product decreased, the increase in related substances during the influencing factor experiment showed a decreasing trend. The stability of the formulation with headspace residual oxygen controlled at 1% to 2% and 2% to 3% was similar, and the increase in impurities and impurities was significantly lower than that of the sample with headspace residual oxygen > 3%. However, further reducing the headspace residual oxygen to below 1% resulted in an even lower increase in impurities and impurities during the influencing factor experiment. Therefore, the headspace residual oxygen was selected to be controlled below 1%.

[0107] The purpose of this invention is to prepare a coenzyme Q10 injection with clinical application value. Three batches of samples (Examples 32, 33, and 34) were prepared based on the prescription and preparation method of Example 28, and stability tests were conducted. The test data are shown in Tables 12-14 below.

[0108] Table 12 shows the results of three batches of high-temperature (60℃) tests.

[0109]

[0110] The results showed that the coenzyme Q10 injection prepared by the present invention has good stability. After being placed at high temperature for 30 days, the properties, pH value and content of the three batches of self-made preparations did not change significantly. However, the related substances showed an increasing trend, and the maximum single impurities and total impurities all increased, indicating that the product is unstable under high temperature conditions.

[0111] Table 13 Results of accelerated testing in three batches of small-scale trials

[0112]

[0113] The results showed that under accelerated 3-month conditions, the largest single impurities and total impurities in the related substances of the self-made and reference formulations increased slightly, while the remaining tested items showed no significant changes. All tested items met the quality standard requirements.

[0114] Table 14 shows the results of three batches of low-temperature cycling and freeze-thaw cycle tests.

[0115]

[0116] The results showed that after 12 days of storage under low temperature and freeze-thaw conditions, there were no significant changes in the properties, related substances, pH value, and content determination of the three batches of self-made samples compared with 0 days, indicating that they were stable under low temperature and freeze-thaw conditions.

[0117] The coenzyme Q10 injection prepared using this invention exhibits good stability. No crystallization occurred during the low-temperature freeze-thaw experiment; after 3 months of accelerated storage, no crystallization or turbidity was observed, and the increase in related substances was not significant. Therefore, controlling the residual oxygen content of the solution to below 2% during formulation preparation is beneficial to the stability of the formulation.

[0118] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of protection of this application is limited to these examples; within the framework of this application, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of different aspects of one or more embodiments of this application as described above, which are not provided in detail for the sake of brevity.

[0119] One or more embodiments in this application are intended to cover all such substitutions, modifications, and variations that fall within the broad scope of this application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of one or more embodiments in this application should be included within the protection scope of this application.

Claims

1. A coenzyme Q10 injection solution, characterized in that, It consists of the following components by weight: 50 parts coenzyme Q10, 800 parts solubilizer, 10-15 parts antioxidant vitamin E, 1-2 parts acidity regulator lactic acid, pH regulator sodium hydroxide and 20,000 parts water for injection. The solubilizer is a mixture of propylene glycol and polyoxyethylene 35 castor oil; the weight ratio of propylene glycol to polyoxyethylene 35 castor oil is 80:18, and the weight ratio of coenzyme Q10 to polyoxyethylene 35 castor oil is 5:

18. The preparation method of the coenzyme Q10 injection is as follows: Coenzyme Q10 is dissolved in a mixed solution of solubilizer and antioxidant, water for injection is added, the mixture is heated and stirred, cooled to room temperature, acidity regulator and pH regulator are added successively to adjust the pH to 3.2~5.5, water for injection is added, the mixture is filtered, filled and sealed, and the residual oxygen after filling is controlled to not exceed 1%. The dissolved oxygen content of the coenzyme Q10 injection is controlled to be less than 1 mg / L; sterilization is performed to obtain the coenzyme Q10 injection.

2. The coenzyme Q10 injection solution as described in claim 1, characterized in that, It also includes 150-300 parts of osmotic pressure regulator.

3. A method for preparing the coenzyme Q10 injection solution as described in claim 1 or 2, characterized in that, Coenzyme Q10 was dissolved in a mixed solution of solubilizer and antioxidant, and water for injection was added. The mixture was heated and stirred, then cooled to room temperature. An acidity regulator and a pH regulator were added sequentially to adjust the pH to 3.2-5.

5. Water for injection was added to make up the volume. The mixture was filtered, filled, and sealed. The residual oxygen after filling was controlled to be no more than 1%, and the dissolved oxygen content of the coenzyme Q10 injection solution was controlled to be less than 1 mg / L. The solution was then sterilized to obtain coenzyme Q10 injection solution.

4. The preparation method according to claim 3, characterized in that, The heating and stirring temperature is 50~70℃.

5. The preparation method according to claim 3, characterized in that, in During the filling process, nitrogen gas is purged before and after filling the drug solution to control the residual oxygen of the sample after filling to not exceed 1%; the filtration method is to pass the sample through microporous membranes of 0.45μm and 0.22μm in sequence.

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