Composition and preparation method of bumetanib injection

Abstract

The invention discloses a composition and a preparation method of bumetanib injection, the prescription of the bumetanib injection comprises bumetanib, xylitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, polyoxyethylene 35 castor oil and water for injection, and the dosage of the polyoxyethylene 35 castor oil is 0.5-1.5 mg / ml. The bumetanib injection disclosed by the invention is simple in composition, stable in quality, simple, convenient and efficient in preparation process and free of special equipment and inert gas filling, and a finished product prepared after terminal sterilization (F0 is greater than or equal to 12) is low in impurity level and good in safety.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a bumetanide injection and a preparation method thereof. Background Art

[0002] Bumetanide, whose chemical name is 3-butylamino-4-phenoxy-5-sulfonylbenzoic acid, is used to treat congestive heart failure, acute pulmonary edema, severe sodium retention and severe hypertension in adults; it can also be used for drug poisoning by salicylates (painkillers) or barbiturates (sleeping pills).

[0003] The chemical structure is shown in the attached Figure 1 .

[0004] Molecular formula: C 17 H 20 N2O5S

[0005] Molecular weight: 364.42

[0006] Bumetanide is a member of the benzoic acid class. Benzoic acid is 4-phenoxybenzoic acid in which the hydrogen adjacent to the phenoxy group is replaced by a butylamino group and an aminosulfonyl group. Bumetanide is a diuretic with indications including: (1) acute pulmonary edema due to congestive heart failure, cirrhosis, nephrotic syndrome, and drugs. (2) as a diuretic for chronic renal insufficiency. (3) drug poisoning requiring forced diuresis.

[0007] Bumetanide is a white crystal or crystalline powder; it is odorless; it dissolves in ethanol and is very slightly soluble in chloroform, but is insoluble in water. Its solubility is greater than 0.1 mg / ml at pH <2.6 or pH >4.9, and its solubility reaches a minimum of 0.038 mg / ml at pH 3.7-3.9. In addition, crystals precipitate from the injection at pH 5.1, and the color of the solution changes after the pH is adjusted to 8-11 and broken down at 100°C for 8 hours. If 5% glucose injection (pH 3.2-6.5) is used for compatibility, there is a risk of precipitation during solution preparation when the pH is low.

[0008] Therefore, it is necessary to find a solubilizer excipient that has good compatibility with bumetanide, can protect the stability of bumetanide in the preparation production and storage environment, and has better safety than other similar solubilizers. Summary of the Invention

[0009] The primary objective of the present invention is to overcome the shortcomings of existing solutions for bumetanide injection by providing a solubilizing agent with excellent solubilization effect and good safety. The present invention also provides a formulation and specific preparation method for the injection, which is simple, efficient, and amenable to large-scale production.

[0010] The object of the present invention is achieved in the following ways:

[0011] A bumetanide injection is characterized in that its prescription composition contains polyoxyethylene 35 castor oil.

[0012] The prescription composition of bumetanide injection is: bumetanide, xylitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, polyoxyethylene 35 castor oil and water for injection.

[0013] The amount of polyoxyethylene 35 castor oil used is preferably 0.5-1.5 mg / ml, more preferably 0.8-1.2 mg / ml, and further preferably 1.0 mg / ml.

[0014] The preparation method of bumetanide injection of the present invention comprises the following steps:

[0015] Add the prescribed amount of bumetanide, xylitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, and polyoxyethylene 35 castor oil to water for injection in sequence, stir until dissolved and clarified, filter through 0.22 μm, fill and seal the ampoules, and sterilize by autoclaving at 121°C for 15 minutes.

[0016] The bumetanide, polyoxyethylene 35 castor oil, xylitol, disodium hydrogen phosphate, and sodium dihydrogen phosphate described in the present invention are all commercially available.

[0017] The solubilizing agent, polyoxyl 35 castor oil, is used in the product of the present invention to effectively increase the solubility of bumetanide and enhance product stability. The hydrophobic components of polyoxyl 35 castor oil account for 83% of the total mixture, primarily polyethylene glycol glycerol ricinoleate. Other hydrophobic components are primarily polyethylene glycol fatty acid esters and unreacted castor oil. The hydrophilic components (17%) are polyethylene glycol and ethoxylated glycerol. Polyoxyl 35 castor oil is a "pure" grade product with low levels of water, potassium, and free fatty acids, thereby enhancing stability. It is worth noting that polyoxyl 35 castor oil is particularly suitable for preparing aqueous solutions of hydrophobic substances.

[0018] The following briefly describes the concept of the present invention:

[0019] Given the poor solubility of bumetanide injection, despite the inclusion of sodium dihydrogen phosphate and disodium hydrogen phosphate buffers in the excipients, prior art methods such as CN112891332A, CN115023223A, and IN2476MUM2011A disclose methods for first dissolving the solution with an alkaline solution, such as sodium hydroxide or potassium hydroxide, and then adjusting the pH to the desired range by adding a buffered saline solution or an acidic solution. This method provides a solution for improving bumetanide solubility, but bumetanide's stability is reduced in alkaline solutions, the dissolution process leads to an increase in impurities, and the preparation process requires the addition of a buffered saline solution or an acidic solution for adjustment, resulting in a complex process and uncontrollable quality. CN103520122A discloses mixing glycerol and water in appropriate proportions to form a cosolvent to increase bumetanide solubility. While this method avoids the problem of using alkaline dissolution and then adding a buffered saline or acid to adjust the pH, the formulation uses activated carbon, which has an adsorption effect on the active ingredient, reducing its content.

[0020] In this regard, the inventors considered three solubilizers and stabilizers, polyoxyethylene 35 castor oil, triolein and benzyl benzoate, and combined them with the sodium dihydrogen phosphate and disodium hydrogen phosphate buffer pair in the original formula to compare the quality indicators of the prepared injections.

[0021]

[0022]

[0023] The test results show that the addition of solubilizers can slightly expand the pH range, while maintaining good drug solubility and stability. Among them, the addition of polyoxyethylene 35 castor oil significantly enhances solubility without affecting the active ingredient content or impurity levels, making polyoxyethylene 35 castor oil superior to other solubilizers.

[0024] L-Polyoxyl (35) Castor oil (CAS: 61791-12-6) is a mixture of castor oil and ethylene oxide (molar ratio = 1:35-40) under high pressure heating and catalytic conditions. The structural formula is shown in the attached Figure 2 .

[0025] Polyoxyethylene 35 castor oil is a pale yellow, viscous liquid that becomes clear and completely liquefied above 26°C. It is soluble in water, fatty acids, oils, mineral oils, and various organic solvents. It is resistant to acids and inorganic salts, and alkalis at low temperatures. Its excellent emulsifying properties make it commonly used as an emulsifier and solubilizer for poorly soluble drugs.

[0026] In order to obtain the most suitable dosage of polyoxyethylene 35 castor oil, multiple schemes were further trial-produced for screening.

[0027]

[0028]

[0029] Test results show that the use of 0.5-1.5 mg / ml of polyoxyethylene 35 castor oil in bumetanide injection shortens the dissolution time of the solution, effectively increases the solubility of bumetanide, and reduces the total impurity content. The preferred formulation is: bumetanide 0.5 mg / ml, polyoxyethylene 35 castor oil 0.5-1.5 mg / ml, xylitol 45 mg / ml, disodium hydrogen phosphate 0.9 mg / ml, and sodium dihydrogen phosphate (as appropriate). More preferred is bumetanide 0.5 mg / ml, polyoxyethylene 35 castor oil 0.8-1.2 mg / ml, xylitol 45 mg / ml, disodium hydrogen phosphate 0.9 mg / ml, and sodium dihydrogen phosphate (as appropriate). Most preferred is bumetanide 0.5 mg / ml, polyoxyethylene 35 castor oil 1.0 mg / ml, xylitol 45 mg / ml, disodium hydrogen phosphate 0.9 mg / ml, and sodium dihydrogen phosphate (as appropriate). BRIEF DESCRIPTION OF THE DRAWINGS Attachment Figure 1

[0025] is the chemical structural formula of Bumetanide. Attachment Figure 2 It is the chemical structural formula of polyoxyethylene 35 castor oil. DETAILED DESCRIPTION

[0030] The present invention is further described with reference to the following embodiments, but the present invention is not limited to these embodiments.

[0031] Example 1

[0032] Per 100,000 mL of bumetanide injection:

[0033] Bumetanide (g) 50 Polyoxyethylene 35 castor oil (g) 50 Xylitol (g) 4500 Disodium hydrogen phosphate (g) 90 Sodium dihydrogen phosphate (g) appropriate amount Add water for injection to (mL) 100000

[0034] The prescribed amount of bumetanide, xylitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, and polyoxyethylene 35 castor oil were added to water for injection in sequence, stirred until dissolved and clarified, filtered through 0.22 μm, filled and sealed in ampoules, and sterilized by autoclaving at 121°C for 15 minutes.

[0035] Example 2

[0036] Per 100,000 mL of bumetanide injection:

[0037] Bumetanide (g) 50 Polyoxyethylene 35 castor oil (g) 80 Xylitol (g) 4500 Disodium hydrogen phosphate (g) 90 Sodium dihydrogen phosphate (g) appropriate amount Add water for injection to (mL) 100000

[0038] The prescribed amount of bumetanide, xylitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, and polyoxyethylene 35 castor oil were added to water for injection in sequence, stirred until dissolved and clarified, filtered through 0.22 μm, filled and sealed in ampoules, and sterilized by autoclaving at 121°C for 15 minutes.

[0039] Example 3

[0040] Per 100,000 mL of bumetanide injection:

[0041] Bumetanide (g) 50 Polyoxyethylene 35 castor oil (g) 100 Xylitol (g) 4500 Disodium hydrogen phosphate (g) 90 Sodium dihydrogen phosphate (g) appropriate amount Add water for injection to (mL) 100000

[0042] The prescribed amount of bumetanide, xylitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, and polyoxyethylene 35 castor oil were added to water for injection in sequence, stirred until dissolved and clarified, filtered through 0.22 μm, filled and sealed in ampoules, and sterilized by autoclaving at 121°C for 15 minutes.

[0043] Example 4

[0044] Per 100,000 mL of bumetanide injection:

[0045] Bumetanide (g) 50 Polyoxyethylene 35 castor oil (g) 120 Xylitol (g) 4500 Disodium hydrogen phosphate (g) 90 Sodium dihydrogen phosphate (g) appropriate amount Add water for injection to (mL) 100000

[0046] The prescribed amount of bumetanide, xylitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, and polyoxyethylene 35 castor oil were added to water for injection in sequence, stirred until dissolved and clarified, filtered through 0.22 μm, filled and sealed in ampoules, and sterilized by autoclaving at 121°C for 15 minutes.

[0047] Example 5

[0048] Per 100,000 mL of bumetanide injection:

[0049] Bumetanide (g) 50 Polyoxyethylene 35 castor oil (g) 150 Xylitol (g) 4500 Disodium hydrogen phosphate (g) 90 Sodium dihydrogen phosphate (g) appropriate amount Add water for injection to (mL) 100000

[0050] The prescribed amount of bumetanide, xylitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, and polyoxyethylene 35 castor oil were added to water for injection in sequence, stirred until dissolved and clarified, filtered through 0.22 μm, filled and sealed in ampoules, and sterilized by autoclaving at 121°C for 15 minutes.

[0051] Example 6

[0052] The products prepared by the prescription process of the technical solution embodiments 1-5 of the present invention meet the requirements in all quality indicators.

[0053]

[0054]

[0055] Example 7

[0056] According to Appendix 9001 "Guidelines for Stability Testing of Raw Materials and Preparations" of Part IV of the 2020 edition of the Chinese Pharmacopoeia, a stability test was conducted on the sample prepared in Example 3 of the optimal combination:

[0057] Accelerated test: Place the sample in a constant temperature and humidity chamber at 40°C and 75% relative humidity for 6 months. Take samples at 1, 2, 3 and 6 months respectively, test them according to the stability investigation items and compare them with the data of 0 month.

[0058] Long-term test: Place the samples under the intermediate conditions of temperature 30℃ and relative humidity 60%, take samples at the 6th and 12th months respectively, test them according to the inspection items, and compare them with the data of month 0.

[0059] The results of the stability test showed that after 6 months of accelerated testing and 12 months of long-term testing, the quality of bumetanide injection met the requirements. The quality of bumetanide injection prepared by the technical solution of the present invention is stable and controllable.

[0060]

Claims

1. A composition of bumetanide injection and a preparation method thereof, characterized in that The formula contains polyoxyethylene 35 castor oil.

2. Polyoxyethylene 35 castor oil according to claim 1, characterized in that The dosage is 0.5-1.5 mg / ml.

3. Polyoxyethylene 35 castor oil according to claim 1, characterized in that The dosage is 0.8-1.2mg / m.

4. Polyoxyethylene 35 castor oil according to claim 1, characterized in that The dosage is 1.0 mg / ml.

5. The bumetanide injection according to claim 1, characterized in that It is composed of bumetanide, polyoxyethylene 35 castor oil, xylitol, disodium hydrogen phosphate and sodium dihydrogen phosphate.

6. The bumetanide injection according to claim 1, wherein the complete preparation process comprises the following steps: Add the prescribed amount of bumetanide, xylitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, and polyoxyethylene 35 castor oil to water for injection in sequence, stir until dissolved and clarified, filter through 0.22 μm, fill and seal the ampoules, and sterilize by hot pressing at 121°C for 15 minutes.

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