Torasemide injection and preparation method thereof

Abstract

The invention provides a torasemide injection and a preparation method thereof, the torasemide injection comprises the following components: torasemide, tromethamine, sodium hydroxide and water for injection, the pH value of the injection is 9.0-10.0, and the components do not contain a solubilizer. The injection provided by the invention has stable physicochemical properties, and the production process is simple.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a torasemide injection and a preparation method thereof. Background Art

[0002] Torasemide is a pyridine-sulfonylurea loop diuretic, with the chemical name of 1-[4-(3-methylanilino)pyridin-3-yl]sulfonyl-3-isopropylurea, which is a white or off-white crystalline powder, and its chemical structure is as follows:

[0003]

[0004] Torasemide injection is a drug applicable to patients with congestive heart failure, liver cirrhosis ascites, and edema caused by kidney diseases. It belongs to a rapid diuretic and has significant curative effects on patients who need rapid diuresis and cannot take diuretics orally.

[0005] The original research specification of torasemide injection clearly lists that its prescription includes torasemide, polyethylene glycol 400 (hereinafter referred to as PEG 400), tromethamine, sodium hydroxide, and water for injection. Impurity F will be generated during the storage of torasemide injection, and the structural formula of impurity F is as follows:

[0006]

[0007] To inhibit the generation of impurity F, it is necessary to strictly control the contact between the liquid medicine and air during the production process or in the final finished product. US4861786 fills nitrogen throughout the liquid medicine preparation process, with the residual oxygen content < 1%, to protect the liquid medicine preparation process, which puts forward high requirements for the filling system and filling parameter control of the nitrogen filling and sealing device for ampoules on the production line. Summary of the Invention

[0008] The purpose of the present invention is to provide a torasemide injection with stable physical and chemical properties and a simplified production process.

[0009] To achieve the above purpose, the present invention provides a torasemide injection, which includes the following components: torasemide, tromethamine, sodium hydroxide, and water for injection, and is characterized in that the pH of the system is 9.0 - 10.0, and the components do not contain solubilizers.

[0010] According to an embodiment of the present invention, the pH of the system in the torasemide injection is 9.5 - 10.0, and further preferably 9.7. A higher pH value helps to maintain better solubility and avoid the risk of product precipitation.

[0011] According to an embodiment of the present invention, the concentration of torasemide in the torasemide injection is 5 mg / ml.

[0012] According to an embodiment of the present invention, the concentration of tromethamine in the torasemide injection is ≤0.5 mg / ml, further preferably, the concentration of tromethamine in the torasemide injection is 0.1 - 0.4 mg / ml, and more preferably 0.125 mg / ml.

[0013] According to an embodiment of the present invention, for the torasemide injection, calculated based on 1000 ml of the injection solution, the formulation components are as follows:

[0014] Component Content Torasemide 5g Trometamol > 0 and ≤ 0.5 g Sodium hydroxide Appropriate amount Water for injection Volume made up to 1000 ml

[0015] The torasemide injection provided by the present invention, when placed for 3 months under the humidity conditions of accelerated test at 40 ± 2°C and 75 ± 5% RH, has no obvious visible foreign matters, the pH value is stable, and impurity F is not detected.

[0016] The present invention also provides a method for preparing a torasemide injection, which includes the following steps:

[0017] 1) Mix a certain amount of water for injection and solid sodium hydroxide, and stir evenly;

[0018] 2) Add the prescribed amounts of torasemide and tromethamine, and stir until completely dissolved;

[0019] 3) Adjust the pH value to 9.0 - 10.0 with sodium hydroxide solution, and stir evenly;

[0020] 4) Add water to make up the volume to the full amount;

[0021] 5) Filter, fill, and melt-seal to obtain the torasemide injection.

[0022] According to an embodiment of the present invention, in step 1), the amounts of water for injection and sodium hydroxide are prepared according to conventional operations so that the torasemide in the prescribed dosage can be dissolved. Generally, the amount of water for injection is about 75% - 85% of the total volume of the prescription; the dosage of sodium hydroxide is about 80% - 100% of the total amount of the prescription. For example, when 800 ml of water is added, about 464 mg - 600 mg of solid sodium hydroxide is added for dissolution.

[0023] Step 1) can be dissolved at room temperature or under heating.

[0024] After adding torasemide and tromethamine in step 2), since torasemide is an acidic substance, the pH value of the system will decrease. Therefore, it is necessary to adjust the pH value to the target value in step 3).

[0025] According to an embodiment of the present invention, in step 3), the pH value is adjusted to 9.5 - 10.0 with sodium hydroxide solution.

[0026] According to an embodiment of the present invention, the target value of pH adjustment with sodium hydroxide solution in step 3) is 9.7.

[0027] According to an embodiment of the present invention, the concentration of the sodium hydroxide solution in step 3) is 0.01 mol / L to 2 mol / L, preferably 0.5 mol / L to 1 mol / L.

[0028] According to an embodiment of the present invention, the filtration method in step 5) is through microporous membranes with pore sizes of 0.45 μm and 0.22 μm.

[0029] According to an embodiment of the present invention, nitrogen filling protection is not required during the preparation of the torasemide injection.

[0030] The present invention provides the following beneficial effects:

[0031] The torasemide injection provided by the present invention improves its solubility by controlling the pH of the solution, without the need to additionally add solubilizers such as PEG400, and there is no need to strictly control the contact between the liquid medicine and air during the production process. Therefore, the production process is simplified and the cost is reduced. The prepared torasemide injection has low impurity content and good stability. Specific Embodiments

[0032] To more fully understand the present invention, the following specific examples are given, but the present invention is not limited to the following examples.

[0033] In this article, unless otherwise stated, % is the percentage of weight / weight (w / w).

[0034] Unless otherwise stated, any numerical value should be understood to be modified by the term "about" in all cases, indicating that such a value can vary within a certain range. When no range is recorded (such as the error range or the standard deviation of the average value given in a chart or data table), the term "about" should be understood to represent a larger range including the recorded value, and the range included by rounding to this number considering significant figures, as well as the range including plus or minus 10% of the recorded value.

[0035] The structural formulas of impurity B and impurity F in the embodiments of the present invention are as follows:

[0036]

[0037] The detection methods of impurity B and impurity F in the embodiments of the present invention are as follows:

[0038] Test solution: Take an appropriate amount of this product and quantitatively dilute it with purified water to prepare a solution containing about 0.1 mg of torasemide per 1 ml.

[0039] Reference solution: Weigh accurately about 25 mg of torasemide reference substance, place it in a 250-ml volumetric flask, dissolve it with purified water and dilute to the mark, shake well. Pipette accurately 1 ml and place it in a 200-ml volumetric flask, dilute to the mark with water and shake well.

[0040] Sensitivity solution: Pipette accurately 1 ml of the reference solution, place it in a 10-ml volumetric flask, dilute to the mark with water and shake well.

[0041] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (YMC Triart C18, 250 mm × 4.6 mm, 3 μm); use 20 mmol / L phosphate buffer solution (pH 3.0) as mobile phase A and acetonitrile as mobile phase B, and perform gradient elution according to the following table; the flow rate is 0.8 ml per minute; the detection wavelength is 291 nm; the column temperature is 30 °C, and the injection volume is 40 μl.

[0042]

[0043] Calculation formula for the contents of impurity B and impurity F

[0044]

[0045] A 杂 : Peak area of a single impurity in the chromatogram of the test solution;

[0046] A 对 : Average peak area of torasemide in the chromatogram of the reference solution;

[0047] W 对 : Weight of torasemide reference substance weighed in the reference solution, mg;

[0048] P 对 : Content of torasemide reference substance;

[0049] V 对 : Dilution factor of the reference solution;

[0050] V 供 : Dilution factor of the test solution;

[0051] f: Impurity correction factor (for impurity B: 0.70, for impurity F: 0.84);

[0052] LC: Theoretical amount of torasemide concentration in torasemide injection, 5 mg / ml.

[0053] Preparation method of torasemide injection in Example 1

[0054]

[0055] The preparation method is as follows:

[0056] (1) Measure 800 ml of water for injection;

[0057] (2) Add 500 mg of sodium hydroxide and stir evenly;

[0058] (3) Add the prescribed amount of torasemide and stir until completely dissolved;

[0059] (4) Add the prescribed amount of tromethamine and stir until completely dissolved;

[0060] (5) Adjust the pH value to 9.7 with sodium hydroxide solution (1 mol / L) and stir evenly; (6) Add water to make up the volume to the full volume;

[0061] (7) Filter, fill, and seal to obtain torasemide injection.

[0062] Preparation method of torasemide injection in Example 2

[0063]

[0064] The preparation method is as follows:

[0065] (1) Measure 800 ml of water for injection;

[0066] (2) Add 500 mg of sodium hydroxide and stir evenly;

[0067] (3) Add the prescribed amount of torasemide and stir until completely dissolved;

[0068] (4) Add the prescribed amount of tromethamine and stir until completely dissolved;

[0069] (5) Adjust the pH value to 9.0 with sodium hydroxide solution (0.5 mol / L) and stir evenly;

[0070] (6) Add water to make up the volume to the full volume;

[0071] (7) Filter, fill, and seal to obtain torasemide injection.

[0072] Preparation method of torasemide injection in Comparative Example 1

[0073]

[0074] The preparation method is as follows:

[0075] (1) Measure 800 ml of water for injection;

[0076] (2) During the preparation process, the preparation container is protected by filling with nitrogen. Sequentially add the prescribed amount of PEG400 and 500 mg of sodium hydroxide and stir evenly;

[0077] (3) Add the prescribed amount of torasemide and stir until completely dissolved;

[0078] (5) Adjust the pH value to 9.0 with sodium hydroxide solution and stir evenly;

[0079] (6) Add water to make up the volume to the full amount;

[0080] (7) Filter, fill, fill with nitrogen, and seal to obtain torasemide injection.

[0081] Preparation method of torasemide injection in Comparative Example 2

[0082]

[0083] The preparation method is as follows:

[0084] (1) Measure 800 ml of injection water;

[0085] (2) During the preparation process, the preparation container is protected by filling with nitrogen. Add the prescribed amounts of PEG400 and 500 mg of sodium hydroxide in sequence and stir evenly;

[0086] (3) Add the prescribed amount of torasemide and stir until completely dissolved;

[0087] (4) Add the prescribed amount of tromethamine and stir until completely dissolved;

[0088] (5) Adjust the pH value to 9.0 with sodium hydroxide solution (0.5 mol / L) and stir evenly;

[0089] (6) Add water to make up the volume to the full amount;

[0090] (7) Filter, fill, fill with nitrogen, and seal to obtain torasemide injection.

[0091] Preparation method of torasemide injection in Comparative Example 3

[0092]

[0093] The preparation method is as follows:

[0094] (1) Measure 800 ml of injection water;

[0095] (2) During the preparation process, the preparation container is protected by filling with nitrogen. Add the prescribed amounts of PEG400 and 500 mg of sodium hydroxide in sequence and stir evenly;

[0096] (3) Add the prescribed amount of torasemide and stir until completely dissolved;

[0097] (4) Add the prescribed amount of tromethamine and stir until completely dissolved;

[0098] (5) Adjust the pH value to 9.0 with sodium hydroxide solution (0.5 mol / L) and stir evenly;

[0099] (6) Make up the volume to the full volume with water;

[0100] (7) Filter, fill, nitrogenize, and melt-seal to obtain torasemide injection.

[0101] Test Example 1:

[0102] Stability test: Place Examples 1, 2, Comparative Example 1, Comparative Example 2, and Comparative Example 3 at (40 ± 2°C, 75 ± 5% RH) under accelerated conditions for 3 months. Sampling is carried out on the 0th day, 10th day, 20th day, 1st month, 2nd month, and 3rd month to detect appearance, visible foreign matters, pH value, impurity B, and impurity F. The stability results of products with different prescriptions are shown in Tables 1, 2, 3, 4, and 5 respectively.

[0103] Table 1

[0104]

[0105]

[0106] NA: Not applicable.

[0107] Table 2

[0108]

[0109] NA: Not applicable.

[0110] Table 3

[0111]

[0112] Table 4

[0113]

[0114] NA: Not applicable.

[0115] Table 5

[0116]

[0117] N.D.: Not detected; NA: Not applicable.

[0118] The above specific embodiments only describe the preferred embodiments of the present invention, rather than limiting the protection scope of the present invention. Without departing from the design concept and spirit of the present invention, various deformations, substitutions, and improvements made by those of ordinary skill in the art to the technical solutions of the present invention according to the written description provided by the present invention shall fall within the protection scope of the present invention. The protection scope of the present invention is determined by the claims.

Claims

1. A torasemide injection, comprising the following components: torasemide, tromethamine, sodium hydroxide, water for injection, characterized in that The pH of the injection is 9.0 to 10.0, and the composition does not contain solubilizers.

2. The injection according to claim 1, characterized in that The pH of the injection is 9.5 - 10.0, more preferably 9.

7.

3. The injection according to claim 1, characterized in that The concentration of torasemide in the injection is 5 mg / ml.

4. The injection according to claim 1, characterized in that The concentration of tromethamine in the injection is ≤0.5 mg / ml, more preferably the concentration of tromethamine in the injection is 0.1 - 0.4 mg / ml, and even more preferably 0.125 mg / ml.

5. The injection according to claim 1, wherein Based on 1000 ml of the injection, the formulation composition is as follows:

6. A method for preparing the torasemide injection according to any one of claims 1 - 5, comprising the following steps: 1) Mix a certain amount of water for injection and solid sodium hydroxide, and stir evenly; 2) Add the prescribed amounts of torasemide and tromethamine, and stir until completely dissolved; 3) Adjust the pH value to 9.0 - 10.0 with sodium hydroxide solution, and stir evenly; 4) Add water to make up the volume to the full amount; 5) Filter, fill, and seal to obtain the torasemide injection.

7. According to the preparation method of claim 6, the amount of water for injection in step 1) is 75% - 85% of the total prescription volume, and the sodium hydroxide is 80% - 100% of the total prescription dosage.

8. According to the preparation method of claim 6, the concentration of the sodium hydroxide solution in step 3) is 0.01 mol / L - 2 mol / L, preferably 0.5 mol / L - 1 mol / L.

9. The preparation method according to claim 6, wherein The filtration method in step 5) is through microporous membranes of 0.45 um and 0.22 um.

10. According to the method of claim 6, the torasemide injection does not require nitrogen protection during the preparation process.

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