Pharmaceutical composition of hydrocortisone sodium succinate for injection and preparation method thereof

Abstract

The invention aims to provide a pharmaceutical composition of hydrocortisone sodium succinate for injection and a preparation method of the pharmaceutical composition. Specifically, the pharmaceutical composition of the hydrocortisone sodium succinate for injection provided by the invention is a freeze-dried powder injection of the hydrocortisone sodium succinate, sodium citrate and sodium chloride.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of hydrocortisone sodium succinate for injection and a preparation method thereof. Background Art

[0002] Hydrocortisone sodium succinate is a short-acting glucocorticoid drug with the same metabolic and anti-inflammatory effects as hydrocortisone. Compared with hydrocortisone, its high water solubility allows for immediate intravenous injection of large doses of hydrocortisone in a small volume of diluent, which is particularly useful in situations where high levels of hydrocortisone are needed quickly. It can be used clinically for emergency treatment of allergies, such as controlling asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity, serum sickness, transfusion reactions and other severe or disabling allergic conditions that are difficult to treat with conventional treatments. It is also commonly used for short-term treatment of acute gouty arthritis. Its structural formula is as follows:

[0003]

[0004] Since hydrocortisone sodium succinate is not stable enough in aqueous solution, it is currently mainly used in clinical practice in the form of powder injection. Its raw materials and lyophilized powder injection have been included in the Chinese Pharmacopoeia 2010 Edition (Part II).

[0005] Hydrocortisone Sodium Succinate for Injection is an injection developed by Pfizer in the 1950s. Due to the technical level at that time, the prescription and dosage were not reasonable. Hydrocortisone Sodium Succinate is unstable in the presence of light and moisture and is very easy to hydrolyze. There is a problem of related substance growth during the preparation and freeze-drying process. Summary of the invention

[0006] The object of the present invention is to provide a pharmaceutical composition of hydrocortisone sodium succinate for injection and a preparation method thereof.

[0007] Specifically, the present invention provides a pharmaceutical composition of hydrocortisone sodium succinate for injection, which is a freeze-dried powder injection of hydrocortisone sodium succinate, sodium citrate and sodium chloride.

[0008] The hydrocortisone sodium succinate pharmaceutical composition for injection provided by the present invention is a lyophilized powder injection, comprising hydrocortisone sodium succinate, sodium citrate and sodium chloride, wherein the pH value of the solution of the lyophilized powder injection after reconstitution is 7.0-8.0.

[0009] The invention discloses a hydrocortisone sodium succinate pharmaceutical composition for injection, comprising hydrocortisone sodium succinate, sodium citrate and sodium chloride, wherein the pH value of the solution thereof is 7.0-8.0, and the composition is a lyophilized powder injection, wherein the weight ratio of hydrocortisone sodium succinate to sodium citrate is 2-5:1, and the weight ratio of hydrocortisone sodium succinate to sodium chloride is 40-50:1, calculated as hydrocortisone.

[0010] In the pharmaceutical composition of the present invention, the weight ratio of hydrocortisone sodium succinate to sodium citrate is 2-5:1 based on hydrocortisone. Preferably, the weight ratio of hydrocortisone sodium succinate to sodium citrate is 4-5:1 based on hydrocortisone.

[0011] In the pharmaceutical composition of the present invention, the weight ratio of hydrocortisone sodium succinate to sodium chloride is 40-50:1 based on hydrocortisone. Preferably, the weight ratio of hydrocortisone sodium succinate to sodium chloride is 40-45:1 based on hydrocortisone.

[0012] In a preferred embodiment, the hydrocortisone sodium succinate pharmaceutical composition for injection provided by the present invention comprises hydrocortisone sodium succinate, sodium citrate and sodium chloride, the pH value of the solution thereof is 7.0-8.0, the composition is a lyophilized powder injection, the weight ratio of hydrocortisone sodium succinate to sodium citrate is 2-5:1, preferably 4-5:1, calculated as hydrocortisone. The weight ratio of hydrocortisone sodium succinate to sodium chloride is 40-50:1, preferably 40-45:1, calculated as hydrocortisone.

[0013] The present invention also provides a method for preparing a hydrocortisone sodium succinate pharmaceutical composition for injection, comprising the following steps:

[0014] a. Take hydrocortisone sodium succinate, sodium citrate and sodium chloride in a weight ratio, place them in a sterile container, add water for injection and stir to dissolve them, and adjust the pH value of the solution to 7.0-8.0;

[0015] b. The solution is sterile filtered through 0.22 μm and aseptically filled into freeze-dried bottles, half-stoppered and transferred to the freeze dryer;

[0016] c. After vacuum freeze-drying at low temperature, plugging, capping and packaging.

[0017] In the above method of the present invention, the composition is a freeze-dried powder injection, the weight ratio of hydrocortisone sodium succinate calculated as hydrocortisone to sodium citrate is 2-5:1, preferably 4-5:1, and the weight ratio of hydrocortisone sodium succinate calculated as hydrocortisone to sodium chloride is 40-50:1, preferably 40-45:1.

[0018] In a preferred embodiment, the present invention provides a method for preparing a hydrocortisone sodium succinate pharmaceutical composition for injection, wherein the composition is a lyophilized powder injection, comprising the following steps:

[0019] a. Take hydrocortisone sodium succinate, sodium citrate and sodium chloride in a weight ratio, wherein the weight ratio of hydrocortisone sodium succinate to sodium citrate is 2-5:1, preferably 4-5:1, and the weight ratio of hydrocortisone sodium succinate to sodium chloride is 40-50:1, preferably 40-45:1, in a sterile container, add water for injection, stir to dissolve, adjust the pH value of the solution to 7.0-8.0, and then add water for injection;

[0020] b. The solution is sterile filtered through 0.22 μm and aseptically filled into freeze-dried bottles, half-stoppered and transferred to the freeze dryer;

[0021] c. After vacuum freeze drying for 24 hours at low temperature, the product is packed, capped and packaged.

[0022] The hydrocortisone sodium succinate pharmaceutical composition for injection and the preparation method thereof have beneficial effects: after adding a small amount of sodium citrate and sodium chloride excipients to the freeze-dried powder injection of the present invention, the growth of related substances during the preparation and freeze-drying process is low, and the photothermal stability is good, the water content is low, and the resolubility is good in clinical use. DETAILED DESCRIPTION

[0023] The following examples are used to further understand the essence of the present invention, but are not intended to limit the scope of the present invention.

[0024] Example 1

[0025] prescription

[0026] Hydrocortisone sodium succinate (calculated as hydrocortisone) 100g

[0027] Sodium citrate 25.8g

[0028] Sodium chloride 2.34g

[0029] Preparation process

[0030] a. Take 13.37g of hydrocortisone sodium succinate (equivalent to 100g of hydrocortisone), 25.8g of sodium citrate and 2.34g of sodium chloride, place them in a sterile container, add 1.8L of water for injection and stir to dissolve them, adjust the pH value of the solution to 7.0-8.0 with dilute hydrochloric acid or sodium hydroxide solution, and add water for injection to 2.0L; b. After 0.22μm sterile filtration, divide them into 7ml freeze-dried bottles at 2ml per bottle and half-stopper them; c. Put them into a freeze dryer for vacuum freeze drying for 20-30 hours, remove the stopper, roll the cap and package.

[0031] Example 2

[0032] prescription

[0033] Hydrocortisone sodium succinate (calculated as hydrocortisone) 10g

[0034] Sodium citrate 2.064g

[0035] Sodium chloride 234mg

[0036] Preparation process

[0037] a. Take 133.7g of hydrocortisone sodium succinate (equivalent to 10g of hydrocortisone), 2.064g of sodium citrate and 234mg of sodium chloride, place them in a sterile container, add 180ml of water for injection and stir to dissolve, adjust the pH value of the solution to 7.0-8.0 with dilute hydrochloric acid or sodium hydroxide solution, and add water for injection to 200ml; b. After 0.22μm sterile filtration, divide them into 7ml freeze-dried bottles at 2ml per bottle and half-stopper them; c. Put them into a freeze dryer for vacuum freeze drying for 20-30 hours, then press the stopper, take them out, roll the cap and package them.

[0038] Example 3

[0039] prescription

[0040] Hydrocortisone sodium succinate (calculated as hydrocortisone) 100g

[0041] Sodium citrate 20.64g

[0042] Sodium chloride 2.34g

[0043] Preparation process

[0044] a. Take 133.7g of hydrocortisone sodium succinate (equivalent to 100g of hydrocortisone), 20.64g of sodium citrate and 2.34g of sodium chloride, place them in a sterile container, add 1.8L of water for injection and stir to dissolve them, adjust the pH value of the solution to 7.0-8.0 with dilute hydrochloric acid or sodium hydroxide solution, and add water for injection to 2.0L; b. After 0.22μm sterile filtration, divide them into 10ml freeze-drying bottles at 5ml per bottle and half-stopper them; c. Put them into a freeze dryer for vacuum freeze drying for 20-30 hours, then press the stopper, take them out, roll the cap and package them.

[0045] Comparative Example 1

[0046] prescription

[0047] Hydrocortisone sodium succinate (calculated as hydrocortisone) 10g

[0048] Anhydrous sodium dihydrogen phosphate 873mg

[0049] Anhydrous disodium hydrogen phosphate 80mg

[0050] a. Take 13.37g of hydrocortisone sodium succinate (equivalent to 10g of hydrocortisone), 873mg of anhydrous sodium dihydrogen phosphate and 80mg of anhydrous disodium hydrogen phosphate, place in a sterile container, add 180ml of water for injection and stir to dissolve, adjust the pH value of the solution to 7.0-8.0 with dilute hydrochloric acid or sodium hydroxide solution, and add water for injection to 200ml; b. After 0.22μm sterile filtration, divide into 7ml freeze-dried bottles at 2ml per bottle and half-stopper; c. Put it into a freeze dryer for vacuum freeze drying for 40-50 hours, then press the stopper, take it out, roll the cap and package it.

[0051] Example 4 Parameter determination

[0052] 1. Water content determination: According to the water content determination method steps recorded in the first method of Appendix VIII M of the 2010 edition of the Chinese Pharmacopoeia, the appearance and water content of the freeze-dried products of Example 1, Example 2, Example 3 and Comparative Example 1 were determined. The results are shown in Table 1:

[0053] Appearance Moisture Reconstitution and clarification Example 1 Loose lumps 1.0％ Easy to reconstitute, clear Example 2 Loose lumps 0.9％ Easy to reconstitute, clear Example 3 Loose lumps 1.0％ Easy to reconstitute, clear Comparative Example 1 Loose lumps 2.6％ Easy to reconstitute, clear

[0054] 2. Determination of related substances and contents: According to the method in the 2010 edition of the Chinese Pharmacopoeia, the related substances and contents of the freeze-dried products of Example 1, Example 2, Example 3 and Comparative Example 1 were determined. The results are shown in Table 2:

[0055] Table 2 Related substances and content results

[0056] Hydrocortisone Total of other impurities content Example 1 0.4％ 0.5％ 100.2％ Example 2 0.3％ 0.4％ 100.6％ Example 3 0.5％ 0.4％ 100.3％ Comparative Example 1 1.8％ 1.2％ 99.2％

[0057] 3. Stability: The freeze-dried samples of Example 1, Example 2, Example 3 and Comparative Example 1 were placed at 60°C and 40°C respectively, and the relevant substances and contents were detected after 10 days. The freeze-dried samples of Example 1, Example 2, Example 3 and Comparative Example 1 were reconstituted and placed at room temperature for 3 days, and the relevant substances and contents were detected. The results are shown in Table 3:

[0058] Table 3 Stability

[0059]

[0060] It can be seen from the above table that the samples prepared according to Examples 1, 2 and 3 are more stable than Comparative Example 1, regardless of whether they are at 40°C, 60°C or in the case of the reconstituted solution.

[0061] The hydrocortisone sodium succinate pharmaceutical composition for injection of the present invention and its preparation method, preferably the freeze-dried powder injection has good stability. Modifications made on the basis of the essence of the present invention all belong to the scope of the present invention.

Claims

1. A pharmaceutical composition of hydrocortisone sodium succinate for injection, comprising hydrocortisone sodium succinate, sodium citrate and sodium chloride, wherein the pH value of the solution is 7.0-8.

0.

2. The pharmaceutical composition according to claim 1, which is a freeze-dried powder injection.

3. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of hydrocortisone sodium succinate to sodium citrate is 2 to 5:1, wherein Hydrocortisone sodium succinate is calculated as hydrocortisone.

4. The pharmaceutical composition according to claim 3, wherein the weight ratio of hydrocortisone sodium succinate to sodium citrate is 4 to 5:1, wherein Hydrocortisone sodium succinate is calculated as hydrocortisone.

5. The pharmaceutical composition according to claim 1 or 2, wherein the weight ratio of hydrocortisone sodium succinate to sodium chloride is 40 to 50:1, wherein Hydrocortisone sodium succinate is calculated as hydrocortisone.

6. The pharmaceutical composition according to claim 5, wherein the weight ratio of hydrocortisone sodium succinate to sodium citrate is 40-45:1, wherein Hydrocortisone sodium succinate is calculated as hydrocortisone.

7. A method for preparing a pharmaceutical composition of hydrocortisone sodium succinate for injection, comprising the following steps: a. Take hydrocortisone sodium succinate, sodium citrate and sodium chloride in a weight ratio, place them in a sterile container, add water for injection and stir to dissolve them, and adjust the pH value of the solution to 7.0-8.0; b. The solution is sterile filtered through 0.22 μm and aseptically filled into freeze-dried bottles, half-stoppered and transferred to the freeze dryer; c. After vacuum freeze-drying at low temperature, plugging, capping and packaging.

8. The method according to claim 7, wherein the weight ratio of hydrocortisone sodium succinate to sodium citrate in step a is 2-5:1, and the weight ratio of hydrocortisone sodium succinate to sodium chloride is 40-50:1, wherein: Hydrocortisone sodium succinate is calculated as hydrocortisone.

9. The method according to claim 8, wherein the weight ratio of hydrocortisone sodium succinate to sodium citrate is 4-5:1, and the weight ratio of hydrocortisone sodium succinate to sodium chloride is 40-45:1.

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