Method for improving stability of diillain acetate preparation

Abstract

The invention relates to a method for improving the stability of a delavain acetate preparation. The preparation method comprises the following steps: mixing auxiliary materials in a solvent, adjusting the pH value to 3.0-4.0, and then adding diillain acetate for dissolving; diluting the obtained solution with a solvent to obtain a diillain acetate solution; introducing protective gas into the obtained diillegal forest acetate solution, so that the dissolved oxygen content in the diillegal forest acetate solution is less than or equal to 1.0 mg / L; the obtained solution is filtered and filled, a container is filled with protective gas, and the residual oxygen content in the container is controlled to be smaller than or equal to 3.0%; and sealing the obtained semi-finished product, sterilizing and carrying out leak detection to obtain the diilacidine acetate preparation. By controlling the pH range of the liquid medicine of the preparation and controlling the preparation processes such as nitrogen introduction in the preparation process and filling and sealing nitrogen charge, the terminal-sterilized diillegal acetic acid preparation is prepared, the quality of the preparation is remarkably improved, the impurity content of the preparation is low, the sterility guarantee level is high, and the adverse effect of high temperature on the preparation can be improved.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and particularly to a method for improving the stability of diphalin acetate preparation. Background Art

[0002] The chemical name of diphalin acetate is 4-amino-1-(phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidine-4-carboxylic acid acetate, which is a κ-opioid receptor (KOR) agonist clinically and can be used to treat moderate to severe pruritus associated with adult chronic kidney disease (CKD-aP) undergoing hemodialysis (HD).

[0003] Diphalin acetate is a synthetic peptide with a single stereoisomer, presenting as a white to off-white powder and existing in the form of acetate. Its structural formula is as follows:

[0004]

[0005] Currently, diphalin acetate injection, a diphalin acetate preparation, is on the market in the United States and the European Union, while there is no preparation on the market in China. However, the preparation on the market in the United States is an injection prepared by a sterile filtration process, with a certain risk of aseptic assurance; the preparation on the market in the European Union is a terminal sterilization preparation with relatively high impurities.

[0006] Therefore, there is an urgent need to provide a method that can effectively inhibit the degradation process of diphalin acetate, reduce the degradation of diphalin acetate during production, storage, and transportation, and improve the stability of the drug. Summary of the Invention

[0007] To solve the above technical problems, the present invention provides a method for improving the stability of diphalin acetate preparation, filling the domestic preparation gap. Compared with the existing diphalin acetate preparations on the market, the present invention can effectively inhibit the degradation process of diphalin acetate by controlling the pH value of the solution during liquid preparation and the protective gas process, reduce the degradation of diphalin acetate during production, storage, and transportation, and improve the stability of the drug. Therefore, the preparation provided by the method of the present invention has a low impurity content, a high aseptic assurance coefficient, can improve the adverse effects of high temperature on the preparation, greatly improves the stability of the preparation during transportation, storage, and use, enhances the safety of diphalin acetate injection preparation, and has obvious clinical advantages.

[0008] The present invention is achieved through the following technical solutions:

[0009] The object of the present invention is to provide a method for improving the stability of diphalin acetate preparation, comprising the following steps:

[0010] (1) Mix the excipients in a solvent, adjust the pH value to 3.0 - 4.0, and then add difluprednate acetate for dissolution;

[0011] (2) Dilute the solution obtained in step (1) with a solvent to obtain a difluprednate acetate solution;

[0012] (3) Introduce a protective gas into the difluprednate acetate solution obtained in step (2) so that the dissolved oxygen content in the difluprednate acetate solution ≤ 1.0 mg / L;

[0013] (4) Filter and fill the solution obtained in step (3), and fill the container with a protective gas, controlling the residual oxygen content in the container ≤ 3.0%;

[0014] (5) Seal, sterilize, and leak-check the semi-finished product obtained in step (4) to obtain a difluprednate acetate preparation.

[0015] In one embodiment of the present invention, in step (1), the excipients are selected from one or more of sodium chloride, potassium chloride, sodium acetate, ammonium acetate, and potassium acetate.

[0016] In one embodiment of the present invention, in step (1), the solvent is selected from one or more of water for injection, propylene glycol for injection, and glycerol for injection.

[0017] In one embodiment of the present invention, in step (1), the pH is adjusted with an acetic acid solution having a concentration of 0.5 mol / L - 5 mol / L.

[0018] In one embodiment of the present invention, in step (2), the concentration of the difluprednate acetate solution is 40 μg / mL - 60 μg / mL (calculated as difluprednate).

[0019] In one embodiment of the present invention, in steps (3) and (4), the protective gas is selected from nitrogen and / or carbon dioxide.

[0020] In one embodiment of the present invention, in steps (3) and (4), the flow rate of the protective gas is 2.0 m 3 / h - 3.0 m 3 / h.

[0021] In one embodiment of the present invention, in step (4), the container is a container that has been sterilized and depyrogenated.

[0022] In one embodiment of the present invention, in step (5), the sterilization conditions are: sterilization at 115°C - 121°C for ≥ 12 min; specifically, sterilization at 121°C for 12 min - 15 min or sterilization at 115°C for ≥ 30 min.

[0023] In one embodiment of the present invention, in step (5), the leak detection is color water leak detection.

[0024] The above technical solution of the present invention has the following advantages compared with the prior art:

[0025] By controlling the pH range of the preparation liquid medicine, as well as controlling the preparation process such as passing nitrogen during the preparation process and filling nitrogen during the filling and sealing process, the present invention prepares an acetate deflazacort injection for terminal sterilization, significantly improving the quality of the preparation, with less impurity content, high aseptic assurance level, and being able to improve the adverse effects of high temperature on the preparation. Specific Embodiments

[0026] The following further illustrates the present invention with specific embodiments, so that those skilled in the art can better understand the present invention and be able to implement it, but the specific embodiments cited do not limit the present invention.

[0027] A method for improving the stability of an acetate deflazacort preparation of the present invention includes the following main steps:

[0028] (1) Dissolve the acetate deflazacort active substance in a solution containing all excipients, adjust the pH value to 3.0 - 4.0 by adding acetic acid solution, dilute with injection water to obtain the required weight, and pass a protective gas;

[0029] (2) Sterilize and filter the final solution;

[0030] (3) Fill the solution into a sterilized and pyrogen-free middle-borosilicate glass ampoule, fill with a protective gas, control the residual oxygen, and seal;

[0031] (4) Sterilize and detect leaks of the semi-finished preparation after filling and sealing to obtain the acetate deflazacort preparation.

[0032] In the acetate deflazacort preparation of the present invention, the concentration of acetate deflazacort (calculated as deflazacort) can be 40 μg / mL - 60 μg / mL; in addition, sodium chloride is selected as the isotonic agent, and the sodium chloride concentration can be 6.5 mg / mL - 7.9 mg / mL; sodium acetate is selected as the buffer, and the sodium acetate concentration can be 2.25 mg / mL - 2.75 mg / mL; acetic acid or glacial acetic acid is also used as the pH regulator, and acetic acid or glacial acetic acid is formulated into an acetic acid solution for further use, and the acetic acid concentration can be 0.5 mol / L - 5 mol / L; the pH regulator adjusts the pH of the liquid medicine in the range of 3.0 - 4.0.

[0033] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods, and the materials, reagents, etc. used, unless otherwise specified, can all be obtained from commercial channels.

[0034] In the embodiments of the present invention, difluprednate acetate is sourced from Suzhou Tianma Pharmaceutical Group Tianji Biopharmaceutical Co., Ltd., with a registration number of Y20240000239 on the registration platform for raw materials, auxiliary materials, and packaging materials at the Center for Drug Evaluation of the National Medical Products Administration. The main batch numbers are 0920221201R and 0920230602.

[0035] Example 1 Research on the protective gas process

[0036] (1) Preparation of difluprednate acetate solution:

[0037] 1) Weigh 12.0 g of glacial acetic acid, dilute it with water for injection, and make up the volume to 100 mL. Mix well to obtain a 2 mol / L acetic acid solution.

[0038] 2) Take 1600 mL of water for injection, dissolve 14.40 g of sodium chloride and 5.00 g of sodium acetate in water successively. Add the 2 mol / L acetic acid solution and adjust the pH of the solution to 4.5.

[0039] 3) Add 0.12 g of difluprednate acetate to the solution obtained in step 2). After stirring and dissolving, make up the volume to 2000 mL with water for injection to obtain the difluprednate acetate solution.

[0040] (2) Protective gas process and sealing

[0041] Table 1

[0042] Batch number 24060901 24060902 24060903 24060904 24060905 Nitrogen purging process (dissolved oxygen) N / A N / A N / A Dissolved oxygen ≤ 1 mg / L Dissolved oxygen ≤ 1 mg / L Nitrogen filling process (residual oxygen) N / A Residual oxygen is about 10% Residual oxygen is about 3% N / A Residual oxygen is about 3%

[0043] According to the design in Table 1 above, conduct research on the protective gas process as follows:

[0044] Take 300 mL of the difluprednate acetate preparation obtained in step (1), directly fill it into 2 mL ampoules with a filling volume of about 1 mL, and seal it by melting. Record the sample batch number as 24060901;

[0045] Take 300 mL of the difluprednate acetate preparation obtained in step (1), fill it into 2 mL ampoules with a filling volume of about 1 mL, then fill the ampoules with nitrogen until the residual oxygen is about 10%, and seal it by melting. Record the sample batch number as 23060902;

[0046] Take 300 mL of the difluprednate acetate preparation obtained in step (1), fill it into 2 mL ampoules with a filling volume of about 1 mL, then fill the ampoules with nitrogen until the residual oxygen is about 3%, and seal it by melting. Record the sample batch number as 24060903;

[0047] Take 300 mL of the difluprednate acetate preparation obtained in step (1), pass nitrogen into the solution until the dissolved oxygen ≤ 1 mg / L, then fill it into 2 mL ampoules with a filling volume of about 1 mL, and seal it by melting. Record the sample batch number as 24060904;

[0048] Take 300 mL of the acetate difluprednate preparation obtained in step (1). After introducing nitrogen into the liquid medicine until the dissolved oxygen ≤ 1 mg / L, fill it into 2-mL ampoules with a filling volume of about 1 mL. Then, fill nitrogen into the ampoules until the residual oxygen is about 3%, and seal it. Record the sample batch number as 24060905.

[0049] (3) Sterilization

[0050] Sterilize the samples of batches 24060901 - 24060905 after the sealing is completed at 121 °C for 15 min, and the acetate difluprednate preparations with different protective gas processes are thus prepared.

[0051] Conduct pH detection and HPLC analysis of related substances on the samples with different protective gas processes. The results are shown in Table 2 below.

[0052] Table 2

[0053]

[0054]

[0055] The above results show that introducing nitrogen into the acetate difluprednate liquid medicine to reduce the dissolved oxygen in the liquid medicine and filling nitrogen during filling to reduce the residual oxygen in the container can both improve the quality and stability of the preparation to a certain extent. The superimposed effect of the two is more significant. Specifically, introducing nitrogen during the preparation of the liquid medicine to make the dissolved oxygen ≤ 1 mg / L and filling nitrogen during sealing to control the residual oxygen ≤ 3.0% can make this product obtain better quality.

[0056] Study on the pH of the liquid medicine in Example 2

[0057] (1) Prepare the acetate difluprednate liquid medicine:

[0058] 1) Weigh 24.0 g of glacial acetic acid, dilute it with water for injection, and make up the volume to 200 mL and mix well to obtain a 2-mol / L acetic acid solution.

[0059] 2) Take 7 portions of 400 mL of water for injection respectively. Each portion dissolves 3.60 g of sodium chloride and 1.25 g of sodium acetate in water successively, and then according to the design in the following table, add 2-mol / L acetic acid solution to adjust the pH of the solution to the values in Table 3. Then add 0.029 g of acetate difluprednate to each portion, stir to dissolve, and make up the volume to 500 mL with water for injection to obtain 7 portions of liquid medicine with different pH values of batches 24061601 - 24061607.

[0060] Table 3

[0061] Batch number 24061601 24061602 24061603 24061604 24061605 24061606 24061607 Adjust pH Do not adjust pH 5.5 pH 5.0 pH 4.5 pH 4.0 pH 3.5 pH 3.0

[0062] (2) Sealing

[0063] The liquid medicines with different pH values obtained in step (1) are respectively filled into vials at a filling volume of about 1 mL per vial and then sealed by melting.

[0064] (3) Sterilization:

[0065] The samples of batches 24061601 - 24061607 after sealing are sterilized at 121 °C for 15 min, and the acetate difluprednate preparations with different pH values are thus prepared.

[0066] The pH values of the samples with different pH values are detected and HPLC analysis of related substances is carried out. The results are shown in Table 4 below.

[0067] Table 4

[0068]

[0069]

[0070] The above results show that when the pH of the solution is adjusted to 4.0 or below, the purity exceeds 99.0%, the levels of RRT1.5 impurity and total impurities are both at relatively low levels, and after high temperature and light exposure, they are also lower than those of samples under the same conditions in other batches. Therefore, it is preferred to adjust the pH of the liquid medicine to 3.0 - 4.0.

[0071] Example 3

[0072] (1) Preparation of acetate difluprednate liquid medicine:

[0073] 1) Weigh 120 g of glacial acetic acid, dilute it with normal temperature injection water, make up the volume to 1 L, and mix well to obtain 2 mol / L acetic acid solution.

[0074] 2) Weigh 24 kg of normal temperature injection water into the liquid preparation tank, successively weigh 216.0 g of sodium chloride and 75.0 g of sodium acetate, dissolve them in water, add 2 mol / L acetic acid solution, adjust the pH of the solution to 3.5, then add 1.5 g of acetate difluprednate (calculated as difluprednate), stir until dissolved, and make up the volume to 30 L with injection water; introduce nitrogen into the liquid medicine until the dissolved oxygen ≤ 1.0 mg / L, and the nitrogen flow rate is 2.0 - 3.0 m 3 / h.

[0075] (2) Filtration and sealing

[0076] After filtering the liquid medicine through a 0.22 - μm polyvinylidene fluoride (PVDF) filter element, it is filled and sealed into 2 - mL middle - borosilicate glass ampoules at a filling volume of 1.05 mL - 1.15 mL, and nitrogen is filled before and after to control the residual oxygen ≤ 3%.

[0077] (3) Sterilization and leak detection

[0078] The samples after sealing are sterilized at 121 °C for 15 min and leak - detected with colored water.

[0079] (5) Visual inspection

[0080] Reject unqualified products such as those without caps or with poor capping, those with filling volume not meeting requirements, those with foreign matters such as glass chips, fibers, and color spots in the bottle, those with scratches on the bottle body, dirty bottles, and broken bottles;

[0081] (6) Labeling, boxing, and packing, the preparation of the desflurane acetate preparation is completed, and the batch number is marked as 24100801.

[0082] Perform pH detection and HPLC analysis of related substances on the sample, and the results are shown in Table 5 below.

[0083] Table 5

[0084]

[0085]

[0086] The above results show that for the preparation prepared according to the process, after various influencing factors, long-term conditions, and accelerated conditions, the number of impurities is small, the impurity level is low, and the change in impurities is not significant. Even after 6 months of acceleration, the total impurities do not exceed 0.5%, and the quality of the preparation is stable and good.

[0087] Example 4

[0088] Prepare 3 batches of samples according to the following process: 24070801, 24070901, 24071001.

[0089] (1) Prepare the desflurane acetate liquid medicine:

[0090] 1) Weigh 12.0 g of glacial acetic acid, dilute it with water for injection, make up the volume to 100 mL, and mix well to obtain a 2 mol / L acetic acid solution.

[0091] 2) Take 2400 mL of water for injection, dissolve 21.60 g of sodium chloride and 7.50 g of sodium acetate in water successively, add the 2 mol / L acetic acid solution, adjust the pH of the solution to about 3.5, then add 0.175 g of desflurane acetate, stir until dissolved, make up the volume to 3000 mL with water for injection, and pass nitrogen into the liquid medicine until the dissolved oxygen ≤ 1.0 mg / L to obtain the desflurane acetate liquid medicine.

[0092] (2) Filtration and sealing:

[0093] Fill a part of the liquid medicine (about 300 mL) into 2 mL middle-borosilicate glass ampoules with a filling volume of about 1.1 mL, fill with nitrogen until the residual oxygen is about 3%, and then seal by melting.

[0094] (3) Sterilization:

[0095] Approximately 300 sealed samples were sterilized at 121°C for 15 minutes, and the preparation of the difluprednate acetate preparation was completed.

[0096] The EU-listed preparation (trade name purchased from Shanghai Zhongzheyuan Biopharmaceutical Co., Ltd.) was compared with batches of preparations prepared in small batches using the process of the present invention under light and high temperature conditions. The results are shown in Table 6; it can be clearly seen that the preparation of the present invention has stable quality and is superior.

[0097] Table 6

[0098]

[0099]

[0100] Obviously, the above embodiments are merely examples for clear illustration and are not limitations on the implementation manners. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to enumerate all the implementation manners here. And the obvious changes or modifications derived therefrom are still within the protection scope of the present invention.

Claims

1. A method for improving the stability of difacillin acetate preparation, characterized in that: The following steps are involved: (1) mixing the auxiliary materials in a solvent, adjusting the pH value to 3.0 to 4.0, and then adding difacillin acetate to dissolve; (2) diluting the solution obtained in step (1) with a solvent to obtain a difacillin acetate solution; (3) introducing a protective gas into the difamoyl acetate solution obtained in step (2) so that the dissolved oxygen content in the difamoyl acetate solution is ≤1.0 mg / L; (4) filtering the solution obtained in step (3), filling the container with protective gas, and controlling the residual oxygen content in the container to ≤3.0%; (5) The semi-finished product obtained in step (4) is sealed, sterilized and leak-checked to obtain the difaconazole acetate preparation.

2. The method according to claim 1, characterized in that In step (1), the auxiliary material is selected from one or more of sodium chloride, potassium chloride, sodium acetate, ammonium acetate and potassium acetate.

3. The method according to claim 1, characterized in that In step (1), the solvent is selected from one or more of water for injection, propylene glycol for injection and glycerol for injection.

4. The method according to claim 1, characterized in that: In step (1), the pH is adjusted by an acetic acid solution having a concentration of 0.5 mol / L to 5 mol / L.

5. The method according to claim 1, characterized in that In step (2), the concentration of the difacillin acetate solution is 40 μg / mL to 60 μg / mL.

6. The method according to claim 1, characterized in that In step (3) and step (4), the protective gas is selected from nitrogen and / or carbon dioxide.

7. The method according to claim 1, characterized in that In step (3) and step (4), the flow rate of the protective gas is 2.0m 3 / h~3.0m 3 / h.

8. The method according to claim 1, characterized in that In step (4), the container is a sterilized and depyrogenated container.

9. The method according to claim 1, characterized in that: In step (5), the sterilization conditions are: sterilization at 115°C to 121°C for ≥12 min.

10. The method according to claim 1, characterized in that In step (5), the leak detection is a colored water leak detection.

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