Dexamethasone sodium phosphate injection and preparation method thereof

Abstract

The invention relates to a dexamethasone sodium phosphate injection and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The preparation method comprises the following steps: 1, sequentially adding glycerol, edetate disodium and dexamethasone sodium phosphate into water for injection according to a weight ratio of (20-25): (0.08-0.12): (4-6), mixing and dissolving, and introducing nitrogen until the dissolved oxygen content is less than or equal to 1mg / L to obtain a liquid medicine 1; step 2, adding a pH regulator into the liquid medicine 1 to regulate the pH value to 7.0-8.5 to obtain liquid medicine 2; and step 3, filtering, filling and sealing the liquid medicine 2, and controlling the residual oxygen content to be less than or equal to 5% to obtain the dexamethasone sodium phosphate injection. Wherein the whole preparation process is protected by inert gas. According to the preparation method of the dexamethasone sodium phosphate injection provided by the invention, the prescription composition of an original drug does not need to be changed, and the prepared dexamethasone sodium phosphate injection can be stably stored at room temperature by adjusting a specific pH range, keeping filling of an inactive gas until the dissolved oxygen content is less than or equal to 1mg / L in the whole preparation process and controlling the residual oxygen content to be less than or equal to 5%.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a dexamethasone sodium phosphate injection and a preparation method thereof. BACKGROUND

[0002] Dexamethasone sodium phosphate injection, commonly known as Dexamethasone Sodium Phosphate Injection, is an adrenal cortex hormone drug with anti-inflammatory, anti-allergic, anti-rheumatic and immunosuppressive effects, and is mainly used for allergic and autoimmune inflammatory diseases. Dexamethasone sodium phosphate injection was first marketed in the United States in October 1959, and then in Japan, Canada and various European countries. The original research drug of the product is listed in the United Kingdom, the certificate holder is Aspen Pharma Trading Limited, the specification is 3.8 mg / ml (calculated as dexamethasone), and the prescription composition is dexamethasone sodium phosphate, glycerol, disodium edetate, phosphoric acid or sodium hydroxide.

[0003] Dexamethasone sodium phosphate is a glucocorticoid drug, but it is easily hydrolyzed to form dexamethasone which is almost insoluble in water, so it has poor stability and is prone to produce impurities during production and storage, affecting the safety of drug use. The original research drug ensures the stability of the drug by reducing the storage temperature to 2-8℃, but for widely used drugs in clinical practice, it increases the social cost.

[0004] Patent CN112245386B uses sodium citrate dihydrate and citric acid as excipients, avoiding the safety problems caused by the addition of organic solvents and antioxidants. By using appropriate amounts of sodium citrate dihydrate and citric acid, the osmotic pressure and pH value of the preparation are ensured, and the stability of the preparation is ensured by using lower liquid preparation temperature, nitrogen filling and sterilization process, solving the problem of drug stability.

[0005] Patent CN104856946B uses sodium citrate instead of propylene glycol in the traditional dexamethasone sodium phosphate injection preparation process, and reduces the amount of sodium bisulfite, which not only ensures the stability of the injection, but also improves the safety of drug use.

[0006] The existing technology solves the problem of the stability of the product by replacing the excipients in the original research drug of the marketed dexamethasone sodium phosphate injection, but the change of the excipients has uncertainty on the quality of the drug, especially the key factors such as bioequivalence. Therefore, how to improve the stability of the drug at room temperature without changing the prescription composition of the original research drug is a problem to be solved. SUMMARY

[0007] To solve the above technical problems, the application provides a preparation method of dexamethasone sodium phosphate injection, which comprises the following steps:

[0008] Step 1: glycerol, disodium edetate and dexamethasone sodium phosphate are sequentially added in water for injection and dissolved to obtain a liquid 1; nitrogen is filled in the liquid 1 until the dissolved oxygen content is less than or equal to 1 mg / L;

[0009] Step 2: a pH regulator is added in the liquid 1 to adjust the pH to 7.0-8.5 to obtain a liquid 2;

[0010] Step 3: the liquid 2 is filtered, filled, sealed and controlled to have a residual oxygen content less than or equal to 5% to obtain the dexamethasone sodium phosphate injection.

[0011] In the preparation process, the whole process is protected by non-active gas.

[0012] In some embodiments, the pH in step 2 is 7.7-8.0.

[0013] In some embodiments, the pH in step 2 is 8.0.

[0014] In some embodiments, the non-active gas is nitrogen or argon.

[0015] In some embodiments, the temperature in steps 1 and 2 is controlled to be 0-30℃.

[0016] In some embodiments, the temperature in steps 1 and 2 is controlled to be 20-25℃.

[0017] In some embodiments, the pH regulator in step 2 is phosphoric acid or sodium hydroxide.

[0018] In some embodiments, the weight ratio of glycerol, disodium edetate and dexamethasone sodium phosphate is 22:0.1:5.

[0019] In some embodiments, the preparation method specifically comprises the following steps:

[0020] Step 1: glycerol, disodium edetate and dexamethasone sodium phosphate are sequentially added in water for injection at a temperature of 0-30℃ and dissolved to obtain a liquid 1; nitrogen is filled in the liquid 1 until the dissolved oxygen content is less than or equal to 1 mg / L;

[0021] Step 2: phosphoric acid or sodium hydroxide is used to adjust the pH to 7.0-8.5 at a temperature of 0-30℃, and the whole process is protected by nitrogen.

[0022] Step 3: filter the medicinal liquid 2 using a 0.22 μm polyether sulfone filter, fill, seal, and control the residual oxygen content to be ≤5%, thereby obtaining the dexamethasone sodium phosphate injection.

[0023] In some embodiments, the step 3 uses a 0.22 μm polyether sulfone filter.

[0024] The beneficial effects of the present application include, but are not limited to, the following:

[0025] 1. The present application provides a preparation method of dexamethasone sodium phosphate injection, which maintains the filling of non-active gas to the dissolved oxygen content ≤1 mg / L and controls the residual oxygen content ≤5% throughout the preparation process, and the prepared injection preparation can be stored at room temperature.

[0026] 2. The present application provides a preparation method of dexamethasone sodium phosphate injection, which controls the pH range of 7.0-8.5 during the preparation process, improves the room temperature storage stability of dexamethasone sodium phosphate injection without changing the prescription composition of the original research drug, and has low process cost and easy implementation.

[0027] 3. The present application provides a dexamethasone sodium phosphate injection, which has good stability, can be stored at room temperature (25℃ or below), and has a preparation quality not lower than the original research. DETAILED DESCRIPTION

[0028] The content of the present application will be further described below in conjunction with specific examples, but should not be understood as a limitation of the present application. If not specifically indicated, the technical means used in the examples are conventional means known to those skilled in the art; the raw materials of the following examples, if not specifically indicated, are obtained by commercial purchase. The original research preparation of the product is selected for marketing in the United Kingdom, the licensed trader is Aspen Pharma Trading Limited, and the specification is 3.8 mg / ml (calculated as dexamethasone). The "room temperature" described in the present application has the meaning known in the art, which is 10-30℃, preferably 20-25℃, and the following examples take 25℃ as an example.

[0029] Example 1

[0030] A dexamethasone sodium phosphate injection includes the following components:

[0031] Prescription composition Dosage Dexamethasone sodium phosphate 1g Glycerin 4.4g Disodium edetate 0.02g Phosphoric acid q.s. Sodium hydroxide q.s. Water for injection q.s. to 200 ml

[0032] Preparation method:

[0033] Step 1: under room temperature conditions, inject nitrogen into water for injection to a dissolved oxygen content ≤1 mg / L, and then add glycerol, disodium edetate, and dexamethasone sodium phosphate in sequence, fully stir and dissolve, to obtain a medicinal liquid 1;

[0034] Step 2: Add phosphoric acid to the liquor 1 to adjust the pH to 7.0 at room temperature, keep the nitrogen filling operation, and protect the whole process with nitrogen gas to obtain liquor 2;

[0035] Step 3: After the liquor 2 is constant volume, it is filtered through a 0.22 μm polyether sulfone filter membrane, then filled and fusion sealed in a 1 ml borosilicate glass ampoule, and the residual oxygen content is controlled to be ≤5%, to obtain the dexamethasone sodium phosphate injection.

[0036] Example 2

[0037] The prescription composition is the same as that of Example 1.

[0038] Preparation method:

[0039] Step 1: Under the condition of room temperature, glycerol, disodium edetate, dexamethasone sodium phosphate are sequentially added to water for injection with dissolved oxygen content ≤1 mg / L, and fully stirred and dissolved to obtain liquor 1;

[0040] Step 2: No pH adjuster is added, and the pH of the liquor 1 is measured to be 7.7, and the whole process is protected with nitrogen gas to obtain liquor 2;

[0041] Step 3: After the liquor 2 is constant volume, it is filtered through a 0.22 μm polyether sulfone filter membrane, then filled and fusion sealed in a 1 ml borosilicate glass ampoule, and the residual oxygen content is controlled to be ≤5%, to obtain the dexamethasone sodium phosphate injection.

[0042] Example 3

[0043] The prescription composition is the same as that of Example 1.

[0044] Preparation method:

[0045] Step 1: Under the condition of room temperature, glycerol, disodium edetate, dexamethasone sodium phosphate are sequentially added to water for injection with dissolved oxygen content ≤1 mg / L, and fully stirred and dissolved to obtain liquor 1;

[0046] Step 2: Under the condition of room temperature, sodium hydroxide is added to the liquor 1 to adjust the pH to 8.0, and the whole process is protected with nitrogen gas to obtain liquor 2;

[0047] Step 3: After the liquor 2 is constant volume, it is filtered through a 0.22 μm polyether sulfone filter membrane, then filled and fusion sealed in a 1 ml borosilicate glass ampoule, and the residual oxygen content is controlled to be ≤5%, to obtain the dexamethasone sodium phosphate injection.

[0048] Example 4

[0049] The prescription composition is the same as that of Example 1.

[0050] Preparation method:

[0051] Step 1: Under the condition of room temperature, nitrogen was filled into water for injection with dissolved oxygen content ≤1 mg / L, and glycerol, disodium edetate, dexamethasone sodium phosphate were sequentially added, and fully stirred and dissolved to obtain a liquid 1;

[0052] Step 2: Under the condition of room temperature, sodium hydroxide was added to the liquid 1 to adjust the pH to 8.5, and the whole process was protected by nitrogen to obtain a liquid 2;

[0053] Step 3: The liquid 2 was constant volume, filtered through a 0.22 μm polyether sulfone filter membrane, then filled and sealed in a 1 ml borosilicate glass ampoule, and the residual oxygen content was controlled to be ≤5%, to obtain a dexamethasone sodium phosphate injection.

[0054] Comparative Example 1:

[0055] It is a reference drug produced by Aspen Pharma Trading Limited company, with a specification of 3.8 mg / ml (calculated as dexamethasone).

[0056] Comparative Example 2:

[0057] The prescription composition is the same as that of Example 1.

[0058] Preparation method:

[0059] Step 1: Under the condition of room temperature, nitrogen was filled into water for injection with dissolved oxygen content ≤1 mg / L, and glycerol, disodium edetate, dexamethasone sodium phosphate were sequentially added, and fully stirred and dissolved to obtain a liquid 1;

[0060] Step 2: No pH adjuster was added, and the pH of the liquid 1 was measured to be 7.7, and the whole process was protected by nitrogen to obtain a liquid 2;

[0061] Step 3: The liquid 2 was constant volume, filtered through a 0.22 μm polyether sulfone filter membrane, then filled and sealed in a 1 ml borosilicate glass ampoule, to obtain a dexamethasone sodium phosphate injection.

[0062] Test Example 1: Test of pH stability of dexamethasone sodium phosphate injection

[0063] Under the same condition of room temperature, the stability was investigated, and the related substance levels of dexamethasone sodium phosphate injection in Examples 1-4 and Comparative Examples 1 were tested and compared, and the comparison results are shown in Table 1.

[0064] Table 1: Comparison results of related substance levels

[0065]

[0066] As can be seen from Table 1, after 1 month of acceleration, impurity A and impurity C in the related substances are greatly affected by pH, and therefore the effects of impurity A and impurity C on the stability of the preparation are investigated. The change trends of impurity A and impurity C are opposite, the growth trend of impurity A decreases with the increase of pH, the growth trend of impurity C increases with the increase of pH, and according to the growth rate of the detection amount of impurities during the stability period, impurity A is greatly affected by pH. Therefore, in order to balance the growth trend of impurity A and impurity C, the pH range of the intermediate is set to 7.0-8.5, preferably pH is 7.7-8.0, and the optimal pH is 8.0. Without changing the prescription composition of the original research drug, the stability of dexamethasone sodium phosphate injection at room temperature is improved, and the quality of dexamethasone sodium phosphate injection can be ensured to be not lower than that of the original research dexamethasone sodium phosphate injection.

[0067] Test Example 2: Test of related substances of dexamethasone sodium phosphate injection with filling, sealing and nitrogen charging stability

[0068] The stability was investigated under the same conditions at room temperature, and the related substance levels of dexamethasone sodium phosphate injection in Example 2 and Comparative Example 2 were tested and compared. The comparison results are shown in Table 2.

[0069] Table 2: Comparison results of related substance levels

[0070]

[0071] The results of Table 2 show that when the residual oxygen content is not controlled during the filling and sealing process, the growth trend of impurity A is much faster than that of the sample with residual oxygen content ≤5% during the acceleration period, and it cannot be stored stably at room temperature. Therefore, in order to ensure product quality, the process with residual oxygen content ≤5% is selected.

[0072] Finally, it should be noted that the above description is only a preferred embodiment of the present application and is not intended to limit the present application. Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent replacements to some technical features, as long as they are within the spirit and principles of the present application. Any modification, equivalent replacement, improvement, etc. made within the scope of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing a dexamethasone sodium phosphate injection solution, characterized by, It comprises the following steps: Step 1: sequentially adding glycerol, disodium edetate and dexamethasone sodium phosphate into water for injection in a weight ratio of 20-25: 0.08-0.12:4-6, dissolving the mixture, filling nitrogen to a dissolved oxygen content of ≤1 mg / L, and obtaining a liquid 1; Step 2: adding a pH adjuster to the liquid 1 to adjust the pH to 7.0-8.5, and obtaining a liquid 2; Step 3: filtering, filling, sealing and controlling the residual oxygen content to ≤5% of the liquid 2, and obtaining the dexamethasone sodium phosphate injection. In the above preparation process, the whole process is protected by non-active gas.

2. The production method according to claim 1, characterized by, The pH in the step 2 is 7.7-8.

0.

3. The preparation method according to claim 1, characterized in that, The pH in the step 2 is 8.

0.

4. The method of claim 1, wherein, The non-active gas is nitrogen or argon.

5. The preparation method according to claim 1, characterized in that, The temperature control in the steps 1 and 2 is 0℃-30℃.

6. The preparation method according to claim 5, characterized in that, The temperature control in the steps 1 and 2 is 20℃-25℃.

7. The preparation method according to claim 1, characterized in that, The pH adjuster in the step 2 is phosphoric acid or sodium hydroxide.

8. The method of claim 1, wherein, The weight ratio of the glycerol, disodium edetate and dexamethasone sodium phosphate is 22:0.1:

5.

9. The production method according to any one of claims 1 to 8, characterized by, It comprises the following steps: Step 1: sequentially adding glycerol, disodium edetate and dexamethasone sodium phosphate into water for injection at a temperature of 0℃-30℃, dissolving the mixture, and obtaining a liquid 1; Step 2: adjusting the pH to 7.0-8.5 using phosphoric acid or sodium hydroxide at a temperature of 0℃-30℃, and obtaining a liquid 2; Step 3: filtering, filling, sealing and controlling the residual oxygen content to ≤5% of the liquid 2, and obtaining the dexamethasone sodium phosphate injection.

10. The dexamethasone sodium phosphate injection obtained by the preparation method of any one of claims 1-9.

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