Fentanyl citrate injection and preparation method thereof

Abstract

The invention discloses a citric acid fentanyl injection and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The formula of the citric acid fentanyl injection comprises an active ingredient citric acid fentanyl, a pH buffering agent, a compound stabilizer, an isoosmotic adjusting agent and solvent water for injection, the compound stabilizer is composed of sodium thiosulfate, citrulline and methyl meglumine, and the sodium thiosulfate, the citrulline and the methyl meglumine cooperate to inhibit degradation of citric acid fentanyl citrate. Through a specific compound stabilizer system and an optimized preparation process, the stability, the dissolution efficiency and the quality uniformity of the injection are remarkably improved, the process steps are clear, parameters are definite, and the injection is suitable for large-scale production and has important clinical value and industrial significance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a fentanyl citrate injection and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Fentanyl citrate, a synthetic phenylpiperidine derivative, is a potent narcotic analgesic widely used in clinical practice. Due to its easy crossing of the blood-brain barrier, it exhibits rapid onset and short duration of action. It primarily exerts its analgesic effect by stimulating μ1 opioid receptors in the central nervous system, with minimal impact on the cardiovascular and gastrointestinal systems. It plays a crucial role in pre-anesthetic medication, induction of anesthesia, intraoperative analgesia, and postoperative pain relief. It is also a commonly used drug in the analgesic and sedative treatment of critically ill patients in the ICU. First synthesized by Dr. Paul Janssen in the late 1950s, it entered clinical practice in the 1960s in an intravenous formulation and has now become one of the core drugs in combined general anesthesia systems and pain management.

[0004] Although fentanyl citrate injection has been used clinically for many years, there are still many shortcomings in the current technology that urgently need to be addressed. These problems directly affect its safety, efficacy, and clinical applicability:

[0005] Firstly, insufficient formulation stability is a core concern. The piperidine ring and amide bond in the fentanyl citrate molecule are susceptible to changes in light, temperature, and pH, and may degrade during storage, potentially increasing the risk of adverse reactions.

[0006] Secondly, there is room for optimization in the formulation process. In existing preparation methods, the drug dissolution process is prone to localized excessively high concentrations, requiring prolonged stirring to ensure uniformity, which reduces production efficiency.

[0007] Against this backdrop, developing a fentanyl citrate injection with excellent stability, higher safety, and efficient preparation process to meet the urgent needs of clinical analgesia is of significant clinical value and industrial importance. Summary of the Invention

[0008] The present invention aims to overcome the technical defects of existing fentanyl citrate injections, such as insufficient stability and low preparation efficiency, and to provide a fentanyl citrate injection with excellent stability, high dissolution efficiency and good quality uniformity, as well as its preparation method, thereby extending the storage period of the preparation, improving the safety and effectiveness of clinical use, and adapting to the needs of large-scale production.

[0009] The core formula of the fentanyl citrate injection of this invention, based on 1000ml of injection, is as follows:

[0010] Active ingredient: Fentanyl citrate 50mg, as the core active ingredient for analgesia; pH buffer: selected from at least one of citrate-sodium citrate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, and acetate-sodium acetate buffer, used to adjust the pH of the injection solution to 4.0-6.0 and maintain the acid-base stability of the system; Stabilizer: a composite stabilizer system is used, including sodium thiosulfate 0.3-0.8g, citrulline 0.2-0.4g, and methylglucamine 0.1-0.5g, which work synergistically to inhibit the degradation of fentanyl citrate; Isotonic adjuster: selected from at least one of sodium chloride, glucose, and mannitol, to maintain the osmotic pressure of the injection solution at 280-320mOsm / kg, matching the physiological osmotic pressure of the human body; Solvent: water for injection, to a final volume of 1000ml.

[0011] The preparation method of the fentanyl citrate injection of the present invention includes the following steps:

[0012] (1) Pretreatment of fentanyl citrate and stabilizer: First grind and mix fentanyl citrate and 1 / 10 of methyl meglumine, add 1 / 5 of citrulline and continue grinding for 5 minutes, then add the remaining stabilizer (including the remaining methyl meglumine, citrulline and all sodium thiosulfate), stir at 300 r / min for 10-20 minutes to obtain a uniform and fine mixture;

[0013] (2) Dissolution and system conditioning: Measure 80% of the prescription amount of water for injection and add it to a sterile preparation vessel. Stir at 200 r / min and control the water temperature at 25-30℃. Add the isotonic regulator and stir for 15 minutes until completely dissolved. Then add the pH buffer and stir for 10 minutes to form a buffer system. Then add the above mixture to the buffer system and stir at 400 r / min for 20-30 minutes until completely dissolved to ensure that the solution is clear, transparent and free of foreign matter.

[0014] (3) Volume adjustment and fine filtration: Add water for injection to 1000ml, stir at 200r / min for 10 minutes, first filter through a 0.45μm filter membrane, and then immediately filter through a 0.22μm filter membrane. Control the filtration flow rate to 5-10ml / min. After filtration, test the pH value and osmotic pressure to ensure that they meet the standards of 4.0-6.0 and 280-320mOsm / kg.

[0015] (4) Filling and sterilization: The above qualified solution is aseptically filled in a filling machine, and then the filled ampoules are placed in a moist heat sterilizer and heated to 121°C at a heating rate of 5°C / min for 15 minutes to obtain the finished product.

[0016] Compared with the prior art, the technical advantages of the present invention are as follows:

[0017] (1) Significantly improved stability: This invention uses a specific ratio of sodium thiosulfate, citrulline, and methylglucamine as a composite stabilizer system, along with a pH buffer, to precisely control the pH of the system, effectively inhibiting the degradation of fentanyl citrate and extending the storage period and circulation range of the formulation.

[0018] (2) Optimization of dissolution efficiency and uniformity: The present invention innovatively adopts a pretreatment process of "gradual grinding + precise stirring". Fentanyl citrate and some stabilizers are premixed and ground first, and then the remaining stabilizers are added and stirred. This effectively avoids the problem of excessive local concentration during drug dissolution and shortens the complete dissolution time to 20-24 minutes.

[0019] (3) The process is adapted to large-scale production: the preparation method has clear steps and parameters. The pretreatment process is highly efficient in coordination with the subsequent dissolution, filtration and sterilization processes. No additional complex equipment is required, which effectively reduces production time and cost. Moreover, the product quality is highly controllable and suitable for large-scale industrial production. Detailed Implementation

[0020] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0021] Example 1: Fentanyl Citrate Injection

[0022] formula:

[0023] Preparation method:

[0024] (1) Pretreatment of fentanyl citrate and stabilizer: Grind and mix fentanyl citrate and 1 / 10 of methylglucamine, add 1 / 5 of citrulline and continue grinding for 5 minutes, then add the remaining stabilizer and stir at 300 r / min for 10-20 minutes to obtain a uniform and fine powder.

[0025] (2) Dissolution and system adjustment: Measure 800ml of water for injection and add it to a sterile preparation tank. Stir at 200r / min and control the water temperature at 25-30℃. Add the isotonic regulator and stir for 15 minutes until completely dissolved. Prepare the pH buffer solution, pour it into the preparation tank, stir for 10 minutes, add the mixed materials, and stir at 400r / min for 20-30 minutes until completely dissolved. The solution is clear, transparent and free of foreign matter.

[0026] (3) Volume adjustment and fine filtration: Add water for injection to 1000 ml and stir at 200 r / min for 10 minutes. After initial filtration through a 0.45 μm filter membrane, immediately filter through a 0.22 μm filter membrane, controlling the flow rate at 5-10 ml / min. Check the pH and osmotic pressure to ensure they meet the standards.

[0027] (4) Filling and sterilization: Place the sterile ampoules in the filling machine for filling and sealing. Then put the ampoules into the moist heat sterilizer and sterilize at 121℃ for 15 minutes. The heating rate is controlled at 5℃ / min.

[0028] Example 2: Fentanyl Citrate Injection

[0029] formula:

[0030] Preparation method:

[0031] (1) Pretreatment of fentanyl citrate and stabilizer: Grind and mix fentanyl citrate and 1 / 10 of methylglucamine, add 1 / 5 of citrulline and continue grinding for 5 minutes, then add the remaining stabilizer and stir at 300 r / min for 10-20 minutes to obtain a uniform and fine powder.

[0032] (2) Dissolution and system adjustment: Measure 800ml of water for injection and add it to a sterile preparation tank. Stir at 200r / min and control the water temperature at 25-30℃. Add the isotonic regulator and stir for 15 minutes until completely dissolved. Prepare the pH buffer solution, pour it into the preparation tank, stir for 10 minutes, add the mixed materials, and stir at 400r / min for 20-30 minutes until completely dissolved. The solution is clear, transparent and free of foreign matter.

[0033] (3) Volume adjustment and fine filtration: Add water for injection to 1000 ml and stir at 200 r / min for 10 minutes. After initial filtration through a 0.45 μm filter membrane, immediately filter through a 0.22 μm filter membrane, controlling the flow rate at 5-10 ml / min. Check the pH and osmotic pressure to ensure they meet the standards.

[0034] (4) Filling and sterilization: Place the sterile ampoules in the filling machine for filling and sealing. Then put the ampoules into the moist heat sterilizer and sterilize at 121℃ for 15 minutes. The heating rate is controlled at 5℃ / min.

[0035] Example 3: Fentanyl Citrate Injection

[0036] formula:

[0037] Preparation method:

[0038] (1) Pretreatment of fentanyl citrate and stabilizer: Grind and mix fentanyl citrate and 1 / 10 of methylglucamine, add 1 / 5 of citrulline and continue grinding for 5 minutes, then add the remaining stabilizer and stir at 300 r / min for 10-20 minutes to obtain a uniform and fine powder.

[0039] (2) Dissolution and system adjustment: Measure 800ml of water for injection and add it to a sterile preparation tank. Stir at 200r / min and control the water temperature at 25-30℃. Add the isotonic regulator and stir for 15 minutes until completely dissolved. Prepare the pH buffer solution, pour it into the preparation tank, stir for 10 minutes, add the mixed materials, and stir at 400r / min for 20-30 minutes until completely dissolved. The solution is clear, transparent and free of foreign matter.

[0040] (3) Volume adjustment and fine filtration: Add water for injection to 1000 ml and stir at 200 r / min for 10 minutes. After initial filtration through a 0.45 μm filter membrane, immediately filter through a 0.22 μm filter membrane, controlling the flow rate at 5-10 ml / min. Check the pH and osmotic pressure to ensure they meet the standards.

[0041] (4) Filling and sterilization: Place the sterile ampoules in the filling machine for filling and sealing. Then put the ampoules into the moist heat sterilizer and sterilize at 121℃ for 15 minutes. The heating rate is controlled at 5℃ / min.

[0042] Comparative Example 1: Fentanyl Citrate Injection

[0043] formula:

[0044] Preparation method:

[0045] Same as in Example 1, but with appropriate adjustments based on changes in stabilizer.

[0046] Comparative Example 2: Fentanyl Citrate Injection

[0047] formula:

[0048] Preparation method:

[0049] Same as in Example 1, but with appropriate adjustments based on changes in stabilizer.

[0050] Comparative Example 3: Fentanyl Citrate Injection

[0051] formula:

[0052] Preparation method:

[0053] Same as in Example 1, but with appropriate adjustments based on changes in stabilizer.

[0054] Comparative Example 4: Fentanyl Citrate Injection

[0055] formula:

[0056] Preparation method:

[0057] Same as in Example 1, but with appropriate adjustments based on changes in stabilizer.

[0058] Comparative Example 5: Fentanyl Citrate Injection

[0059] formula:

[0060] Preparation method:

[0061] Same as in Example 1, but with appropriate adjustments based on changes in stabilizer.

[0062] Comparative Example 6: Fentanyl Citrate Injection

[0063] formula:

[0064] Preparation method:

[0065] Same as in Example 1, but with appropriate adjustments based on changes in stabilizer.

[0066] Comparative Example 7: Fentanyl Citrate Injection

[0067] formula:

[0068] Preparation method:

[0069] Same as in Example 1, but with appropriate adjustments based on changes in stabilizer.

[0070] Comparative Example 8: Fentanyl Citrate Injection

[0071] formula:

[0072] Same as Example 1.

[0073] Preparation method:

[0074] (1) Dissolution and system adjustment of fentanyl citrate: Measure 800 ml of water for injection and add it to a sterile preparation vessel. Stir at 200 r / min and control the water temperature at 25-30℃. Add isotonic regulator and stir for 15 minutes until completely dissolved. Prepare pH buffer solution and inject it into the preparation vessel. Stir for 10 minutes and add fentanyl citrate, sodium thiosulfate, citrulline and methylglucamine. Stir at 400 r / min for 20-30 minutes until completely dissolved. The solution is clear, transparent and free of foreign matter.

[0075] (2) Volume adjustment and fine filtration: Add water for injection to 1000 ml and stir at 200 r / min for 10 minutes. After initial filtration through a 0.45 μm filter membrane, immediately filter through a 0.22 μm filter membrane, controlling the flow rate at 5-10 ml / min. Check the pH and osmotic pressure to ensure they meet the standards.

[0076] (3) Filling and sterilization: Place the sterile ampoules in the filling machine for filling and sealing. Then put the ampoules into the moist heat sterilizer and sterilize at 121℃ for 15 minutes. The heating rate is controlled at 5℃ / min.

[0077] Stability test of fentanyl citrate injection

[0078] The content of fentanyl citrate was determined according to the High Performance Liquid Chromatography (HPLC) method (General Chapter 0512) of the Pharmacopoeia of the People's Republic of China. Test solution: Take this product directly. Reference solution: Accurately weigh an appropriate amount of fentanyl citrate reference standard, dissolve it in water, and quantitatively dilute it to prepare a solution containing approximately 50 μg per ml. Chromatographic conditions: Use octadecylsilane-bonded silica gel as the stationary phase; use a mobile phase of a solution containing 0.1% anhydrous sodium sulfate and 0.2% ammonium acetate - methanol - acetonitrile (4:3:1) (adjust the pH to 6.3±0.1 with glacial acetic acid); the detection wavelength is 220 nm; the injection volume is 20 μl. System suitability requirements: The theoretical plate number, calculated based on the fentanyl peak, should not be less than 2500. Determination method: Accurately measure the test solution and reference solution, inject them separately into the HPLC system, and record the chromatograms. Calculate the content based on peak area using the external standard method.

[0079] Accelerated test conditions: temperature 40℃±2℃, relative humidity 75%±5%, 6 months.

[0080] Table 1. Accelerated Test Fentanyl Citrate Content

[0081] Table 1 shows that, under accelerated testing conditions, the fentanyl citrate injection solutions described in Examples 1-3 of this invention effectively maintain the stability of the core drug components, and the drug content retention effect is significantly better than that of Comparative Examples 1-8 and commercially available formulations. This invention, through a specific combination of stabilizers and pretreatment processes, significantly improves the anti-degradation ability of the formulation under harsh storage conditions, ensuring the stability of the drug's efficacy.

[0082] Long-term test conditions: temperature 25℃±2℃, relative humidity 60%±10%, 12 months.

[0083] Table 2. Fentanyl citrate content in long-term trials

[0084] Table 2 shows that under long-term storage conditions, the stability advantage of the fentanyl citrate injection of this invention remains prominent. During a 12-month storage period, the content of the active pharmaceutical ingredient decreases only slightly, maintaining a stable level of efficacy over a long period. This further confirms that the specific stabilizer ratio and preparation process used in this invention can effectively resist the influence of environmental factors on the drug during long-term storage, significantly extending the effective storage period of the formulation and improving the reliability of clinical applications.

[0085] Comparative experiment on the dissolution of fentanyl citrate injection

[0086] Stirring, dissolving, and index detection

[0087] (1) Start the dissolution timer: Quickly add the pretreated mixture (or the untreated material of Comparative Example 8, directly weigh fentanyl citrate and all stabilizers and add them) into the buffer system, immediately start the electronic stopwatch, and at the same time adjust the stirring speed to 400 r / min and continue stirring;

[0088] (2) Complete dissolution time record: Observe the state of the solution every 30 seconds, and judge whether it is completely dissolved by visual observation + microscopic observation (100x) (standard: the solution is clear and transparent, and no undissolved particles are visible under the microscope). Record the time from the addition of the material to complete dissolution (unit: min).

[0089] (3) Turbidity detection after dissolution: After complete dissolution, the turbidity (NTU) of the solution is measured using a turbidity meter. The measurement is repeated 3 times and the average value is taken.

[0090] (4) Homogeneity test: Use a pipette to take 1 ml of each of the upper layer (1 cm from the liquid surface), middle layer (middle of the liquid surface), and lower layer (1 cm from the bottom of the cup) of the solution. Determine the fentanyl citrate content according to the HPLC method of the Pharmacopoeia of the People's Republic of China. Calculate the relative standard deviation (RSD) of the content at the three sampling points. RSD ≤ 2.0% is considered to be homogeneous and qualified.

[0091] Table 3. Record of Measured Data for Key Solubility Indicators

[0092] Table 3 shows that the composite stabilizer combination of sodium thiosulfate, citrulline, and methylglucamine of this invention, combined with the grinding and fractionation mixing process, significantly optimizes the stirring and dissolving process of fentanyl citrate injection, and can simultaneously improve dissolution efficiency and quality: (1) Shortening dissolution time and improving production efficiency: This process combination can significantly accelerate the dissolution rate of fentanyl citrate. Compared with comparative examples 1-8, the dissolution time is significantly shortened, effectively reducing production time costs and providing strong support for large-scale production of the preparation. (2) Optimizing solution quality and consolidating the foundation of the preparation: After treatment by this process, the clarity and concentration uniformity of the solution are significantly better than those of the comparative examples, ensuring that the preparation meets the pharmaceutical standard requirements. The synergistic effect of the composite stabilizer and pretreatment process of this invention precisely solves the technical pain points such as slow dissolution and poor uniformity in the preparation of fentanyl citrate injection, and has clear process optimization value and important industrial application prospects.

Claims

1. A fentanyl citrate injection solution, characterized in that, The fentanyl citrate injection solution, calculated per 1000 ml injection volume, includes 50 mg of the active ingredient fentanyl citrate, as well as a pH buffer, stabilizer, isotonic adjuster, and water for injection as the solvent; the stabilizer is sodium thiosulfate, citrulline, and methylglucamine.

2. The fentanyl citrate injection solution according to claim 1, characterized in that, The stabilizer is sodium thiosulfate 0.3-0.8g, citrulline 0.2-0.4g, and methylglucamine 0.1-0.5g.

3. The fentanyl citrate injection solution according to claim 1, characterized in that, The pH buffer is selected from at least one of citric acid-sodium citrate buffer, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer, and acetate-sodium acetate buffer.

4. The fentanyl citrate injection solution according to claim 1, characterized in that, The isotonic regulator is selected from at least one of sodium chloride, glucose, and mannitol.

5. The fentanyl citrate injection solution according to claim 1, characterized in that, The pH buffer is used to adjust the pH of the fentanyl citrate injection to 4.0-6.

0.

6. The fentanyl citrate injection solution according to claim 1, characterized in that, The isotonic regulator maintains the osmotic pressure of fentanyl citrate injection at 280-320 mOsm / kg.

7. The method for preparing fentanyl citrate injection according to claim 1, characterized in that, The preparation method includes the following steps: (1) Pretreatment of fentanyl citrate and stabilizer: Grind and mix fentanyl citrate and 1 / 10 of methylglucamine, add 1 / 5 of citrulline and continue grinding for 5 min, then add the remaining stabilizer and stir at 300 r / min for 10-20 min to obtain the mixture; (2) Dissolution and system conditioning; (3) Volume adjustment and fine filtration; (4) Filling and sterilization.

8. The preparation method according to claim 7, characterized in that, The dissolution and system conditioning steps are as follows: Preparation of buffer system and isotonicity regulator: Add 80% of the prescribed amount of water for injection, add isotonicity regulator, stir, add pH buffer, stir to obtain buffer system, add the mixture to buffer system, and stir.

9. The preparation method according to claim 7, characterized in that, The volume adjustment and fine filtration steps are as follows: add water for injection to 1000ml, stir, and filter.

10. The preparation method according to claim 7, characterized in that, The filling and sterilization steps are as follows: filling, sterilization at 121°C for 15 minutes.

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