A preparation method of stable ketorolac tromethamine injection

Abstract

The present invention discloses a method for preparing a ketorolac tromethamine injection with improved stability. The method comprises treating the main ingredient ketorolac tromethamine with liquid nitrogen, and then adding water for injection, sodium chloride, ethanol, sodium dihydrogen phosphate, or citric acid as an excipient to prepare the injection. Compared with the prior art, the method improves the stability of the ketorolac tromethamine injection, and shows minimal increase in related substances in an accelerated test over six months.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a method for preparing a ketorolac tromethamine injection with improved stability. Background Art

[0002] Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that inhibits prostaglandin synthesis, resulting in analgesic effects. Clinically, it is primarily indicated for the short-term treatment of acute, severe pain requiring opioid-level analgesics. It is typically used for postoperative analgesia and is not suitable for mild or chronic pain.

[0003] Ketorolac tromethamine has been developed into an injection and is available both domestically and internationally. Trade names include Shangruixin and Nisong. Because ketorolac tromethamine injection is susceptible to oxidation, the presence of related substances may increase during long-term storage. For example, Chinese patent CN101199514B discloses a method for preparing ketorolac tromethamine injection, in which nitrogen is added to the ampoule before potting to reduce oxidation of the ketorolac tromethamine. However, after six months in an accelerated test (40°C ± 2°C / RH 75% ± 5%), the presence of related substances increased from 0.22% to 0.49%.

[0004] Chinese patent CN201010115368.4 discloses a ketorolac tromethamine injection in which nitrogen is introduced into the solution before filling to reduce oxidation of the ketorolac tromethamine. However, in accelerated testing (25°C ± 2°C / RH 60% ± 10%), the levels of related substances increased after six months, as well as in long-term testing.

[0005] In order to solve the problem that the existing injection still has the problem of related substances increasing after long-term storage, the inventors have improved the preparation process of the injection, thereby solving the problem of significant increase of related substances. Summary of the Invention

[0006] The present invention aims to provide a method for preparing a stable ketorolac tromethamine injection, wherein the method improves the stability of the ketorolac tromethamine injection and shows a small increase in related substances in an accelerated test for six months.

[0007] To achieve the purpose of the present invention, the following embodiments are provided:

[0008] The present invention provides a method for preparing a stable ketorolac tromethamine injection, comprising the following steps:

[0009] 1) Weigh the prescribed amount of ketorolac tromethamine, place it in a liquid preparation container, add liquid nitrogen, and soak for 5-10 minutes;

[0010] 2) Add the prescribed amount of water for injection, the prescribed amount of sodium chloride, and the prescribed amount of ethanol or sodium dihydrogen phosphate or citric acid to the liquid preparation container and stir to dissolve completely;

[0011] 3) Fill the ampoule with nitrogen, then add the remaining amount of water for injection, adjust the pH with sodium hydroxide or potassium hydroxide solution, and filter until the solution is clear;

[0012] 4) Fill the clarified liquid medicine obtained in step 3), seal the container, and sterilize.

[0013] Preferably, in the preparation method of the present invention, the amount of liquid nitrogen added in step 1) is 0.8-2 times the amount of ketorolac tromethamine, preferably 1 time (equivalent); in step 2), the portion of water for injection is 60-80% of the prescribed amount, more preferably 80% of the prescribed amount, and the stirring time is 10-15 minutes; and in step 3), the pH is adjusted to 7.3-7.6.

[0014] Preferably, in the preparation method of the present invention, the sterilization in step 4) is performed by circulating steam sterilization at 121° C. for 15 minutes.

[0015] The preparation method of the present invention further comprises inspecting the sterilized drugs in step 4) and packaging qualified drugs for storage.

[0016] In one embodiment, the method for preparing a stable ketorolac tromethamine injection of the present invention comprises the following steps:

[0017] 1) Weigh the prescribed amount of ketorolac tromethamine, place it in a dedicated liquid preparation tank, add an equal amount of liquid nitrogen, and soak for 5-10 minutes;

[0018] 2) Add 80% of the prescribed amount of water for injection, the prescribed amount of sodium chloride, and the prescribed amount of ethanol or sodium dihydrogen phosphate or citric acid to the dispensing tank and stir for 10-15 minutes until completely dissolved;

[0019] 3) Add water for injection to the prescribed amount, stir for 10-15 minutes, adjust the pH to 7.3-7.6 with sodium hydroxide solution, and filter with a 0.22 μm polyethersulfone filter until the solution is clear;

[0020] 4) Fill each clean brown borosilicate glass ampoule with nitrogen, fill with the drug solution, and seal;

[0021] 5) Sterilize with circulating steam at 121°C for 15 minutes;

[0022] 6) Inspect the sterilized drugs and pack the qualified ones into storage.

[0023] The method of the present invention treats the main drug ketorolac tromethamine with liquid nitrogen, thereby fully replacing oxygen trapped in the raw material and sealing the raw material ketorolac tromethamine. Then, auxiliary materials are added to prepare the injection. Compared with the existing technology and directly filling the liquid preparation tank (solid raw material) with nitrogen, the stability of the ketorolac tromethamine injection is improved. In particular, in an accelerated test for six months, the increase of related substances is substantially eliminated. DETAILED DESCRIPTION

[0024] The essence of the present invention can be better understood through the following examples. The following examples are used to illustrate and understand the spirit of the present invention, but should not be construed as limiting the scope of the present invention.

[0025] Example 1

[0026]

[0027] Preparation process:

[0028] 1. Take the prescribed amount of ketorolac tromethamine, place it in a special liquid preparation tank, add an equal amount of liquid nitrogen, and soak for 8 minutes.

[0029] 2. Add 4L of water for injection and the prescribed amount of sodium chloride and ethanol to the preparation tank, stir for 10 to 15 minutes, and visually check for complete dissolution.

[0030] 3. Add water for injection to the prescribed amount, stir for 10 to 15 minutes, adjust the pH to 7.3 to 7.4 with 10% (w / w) sodium hydroxide solution, and filter through a 0.22 μm polyethersulfone filter until the solution is clear.

[0031] 4. Fill each clean brown borosilicate glass ampoule with nitrogen, fill it with the drug solution, and seal it.

[0032] 5. Sterilize with circulating steam at 121°C for 15 minutes.

[0033] 6. Inspect the sterilized drugs and pack and store qualified products.

[0034] Comparative Example 1

[0035]

[0036] Preparation process:

[0037] 1. Weigh the prescribed amount of ketorolac tromethamine and place it in a special liquid preparation tank.

[0038] 2. Add 4L of water for injection and the prescribed amount of sodium chloride and ethanol to the preparation tank, stir for 10 to 15 minutes, and visually check for complete dissolution.

[0039] 3. Add water for injection to the prescribed amount, stir for 10 to 15 minutes, adjust the pH to 7.3 to 7.4 with 10% (w / w) sodium hydroxide solution, and filter through a 0.22 μm polyethersulfone filter until the solution is clear.

[0040] 4. Fill each clean brown borosilicate glass ampoule with nitrogen, fill it with the drug solution, and seal it.

[0041] 5. Sterilize with circulating steam at 121°C for 15 minutes.

[0042] 6. Inspect the sterilized drugs and pack and store qualified products.

[0043] Example 2

[0044]

[0045] Preparation process:

[0046] 1. Weigh the prescribed amount of ketorolac tromethamine, place it in a special liquid preparation tank, add 0.8 times the amount of liquid nitrogen, and soak for 10 minutes.

[0047] 2. Add 4L of water for injection and the prescribed amount of sodium chloride and sodium dihydrogen phosphate to the preparation tank, stir for 10 to 15 minutes, and visually check for complete dissolution.

[0048] 3. Add water for injection to the prescribed amount, stir for 10 to 15 minutes, adjust the pH to 7.4 to 7.5 with 10% (w / w) sodium hydroxide solution, and filter through a 0.22 μm polyethersulfone filter until the solution is clear.

[0049] 4. Fill each clean brown borosilicate glass ampoule with nitrogen, fill it with the drug solution, and seal it.

[0050] 5. Sterilize with circulating steam at 121°C for 15 minutes.

[0051] 6. Inspect the sterilized drugs and pack and store qualified products.

[0052] Comparative Example 2

[0053]

[0054]

[0055] Preparation process:

[0056] 1. Weigh the prescribed amount of ketorolac tromethamine, place it in a special liquid preparation tank, and continuously fill the ketorolac tromethamine solid with nitrogen for 10 minutes.

[0057] 2. Add 4L of water for injection and the prescribed amount of sodium chloride and sodium dihydrogen phosphate to the preparation tank, stir for 10 to 15 minutes, and visually check for complete dissolution.

[0058] 3. Add water for injection to the prescribed amount, stir for 10 to 15 minutes, adjust the pH to 7.4 to 7.5 with 10% (w / w) sodium hydroxide solution, and filter through a 0.22 μm polyethersulfone filter until the solution is clear.

[0059] 4. Fill each clean brown borosilicate glass ampoule with nitrogen, fill it with the drug solution, and seal it.

[0060] 5. Sterilize with circulating steam at 121°C for 15 minutes.

[0061] 6. Inspect the sterilized drugs and pack and store qualified products.

[0062] Example 3

[0063]

[0064] Preparation process:

[0065] 1. Weigh the prescribed amount of ketorolac tromethamine, place it in a special liquid preparation tank, add 2 times the amount of liquid nitrogen, and soak for 5 minutes.

[0066] 2. Add 3L of water for injection and the prescribed amount of sodium chloride and citric acid to the preparation tank, stir for 10 to 15 minutes, and visually check for complete dissolution.

[0067] 3. Add water for injection to the prescribed amount, stir for 10 to 15 minutes, adjust the pH to 7.5 to 7.6 with 10% (w / w) potassium hydroxide solution, and filter through a 0.22 μm polyethersulfone filter until the solution is clear.

[0068] 4. Fill each clean brown borosilicate glass ampoule with nitrogen, fill it with the drug solution, and seal it.

[0069] 5. Sterilize with circulating steam at 121°C for 15 minutes.

[0070] 6. Inspect the sterilized drugs and pack and store qualified products.

[0071] Comparative Example 3

[0072]

[0073] Preparation process:

[0074] 1. Weigh the prescribed amount of ketorolac tromethamine and place it in a special liquid preparation tank.

[0075] 2. Add 3L of water for injection and the prescribed amount of sodium chloride and citric acid to the preparation tank, stir for 10 to 15 minutes, and visually check for complete dissolution.

[0076] 3. Add water for injection to the prescribed amount, stir for 10 to 15 minutes, adjust the pH to 7.5 to 7.6 with 10% (w / w) potassium hydroxide solution, and filter through a 0.22 μm polyethersulfone filter until the solution is clear.

[0077] 4. Fill each clean brown borosilicate glass ampoule with nitrogen, fill it with the drug solution, and seal it.

[0078] 5. Sterilize with circulating steam at 121°C for 15 minutes.

[0079] 6. Inspect the sterilized drugs and pack and store qualified products.

[0080] Stability test

[0081] The samples of the examples and comparative examples were subjected to accelerated stability tests to compare the stability of the samples.

[0082] Test method: Place at a temperature of 40±2℃ and a relative humidity of 75±5% for 3 months. Take samples once in the 1st, 2nd and 3rd month of the experiment, and determine the relevant substances by high performance liquid chromatography. Compare with the results in 0 month. The results are shown in Table 1.

[0083] Table 1 Accelerated stability test results of samples of Examples and Comparative Examples

[0084]

[0085]

[0086] The results show that compared with the corresponding samples of Comparative Examples 1 to 3, the samples of Examples 1 to 3 prepared by the method described in the present invention have significantly improved stability.

[0087] Any simple changes and modifications made within the spirit of the present invention also fall within the scope of protection of the present invention.

Claims

1. A method for preparing a stable ketorolac tromethamine injection, comprising the following steps: 1) Weigh the prescribed amount of ketorolac tromethamine, place it in a liquid preparation container, add liquid nitrogen, and soak for 5-10 minutes; 2) Add the prescribed amount of water for injection, the prescribed amount of sodium chloride, and the prescribed amount of ethanol or sodium dihydrogen phosphate or citric acid to the liquid preparation container and stir to dissolve completely; 3) Add the remaining amount of water for injection, adjust the pH with sodium hydroxide or potassium hydroxide solution, and filter until the solution is clear; 4) Fill the ampoule with nitrogen, then fill it with the clarified liquid medicine from step 3), seal it, and sterilize it. in, The amount of liquid nitrogen added in step 1) is 0.8-2 times the amount of ketorolac tromethamine, and the stirring time for the stirring and dissolving in step 2) is 10-15 minutes.

2. The preparation method according to claim 1, wherein the amount of liquid nitrogen added in step 1) is comparable to the amount of ketorolac tromethamine.

3. The preparation method according to claim 1, wherein the partial water for injection is 60-80% of the prescription amount.

4. The preparation method according to claim 3, wherein the partial water for injection is 80% of the prescription amount.

5. The preparation method according to claim 1, wherein the pH is adjusted to 7.3-7.6 in step 3).

6. The preparation method according to claim 1, wherein the sterilization in step 4) is performed by circulating steam sterilization at 121°C for 15 minutes.

7. The preparation method according to claim 1, further comprising inspecting the sterilized drugs in step 4) and packaging qualified drugs for storage.

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