Dexmedetomidine hydrochloride injection and preparation process thereof

Abstract

This invention belongs to the field of pharmaceutical preparations, specifically relating to a dexmedetomidine hydrochloride injection and its preparation process. The dexmedetomidine hydrochloride injection comprises dexmedetomidine hydrochloride, sodium chloride, a metal ion chelating agent, a stabilizer, and water for injection. The metal ion chelating agent is sodium gluconate, and the stabilizer is Tween-80. This invention, by adding a metal ion chelating agent and a stabilizer, screening their types, and optimizing the preparation process of the injection, yields a dexmedetomidine hydrochloride injection that exhibits good stability during long-term storage, without discoloration, pH stability, or stability of related substances. Furthermore, the preparation process is simple and easy to operate, facilitating industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology and relates to a dexmedetomidine hydrochloride injection and its preparation process. Background Technology

[0002] Dexmedetomidine hydrochloride is an α2-adrenergic receptor agonist, chemically named (+)-4-(S)-1-(2,3-dimethylphenyl)ethyl-1H-imidazolium hydrochloride. α2-adrenergic receptors are widely distributed in the central nervous system, peripheral nerves, and autonomic ganglia. Studies have shown that excitation of presynaptic α2-adrenergic receptors at sympathetic nerve endings can inhibit the release of norepinephrine. α2-agonists in the central nervous system can activate postsynaptic receptors, reducing sympathetic activity and thus lowering blood pressure and heart rate. Reduced sympathetic efferent activity can decrease the required dosage of anesthetic drugs. Dexmedetomidine hydrochloride has unique advantages compared to other sedatives, being 7-8 times more potent than clonidine. It possesses strong sedative, analgesic, anti-anxiety, and sympathetic nerve activity-inhibiting pharmacological effects, and features intraoperative arousal, no respiratory depression, and stable perioperative hemodynamics. It also significantly reduces postoperative side effects such as shivering, nausea, and vomiting. Currently, dexmedetomidine hydrochloride injection is available in small-volume injections of 1ml and 2ml.

[0003] However, dexmedetomidine hydrochloride is easily affected by light and metal ions. During storage, the injection solution is prone to problems such as darkening of color, pH instability, and increase of related substances, resulting in poor stability and posing certain difficulties for large-scale production. How to screen suitable formulations and optimize the preparation process to ultimately ensure that dexmedetomidine hydrochloride injection solution does not change color, maintains pH stability, and has stable related substances during long-term storage, and thus maintains stable product quality, is an urgent problem for pharmaceutical manufacturers to solve. Summary of the Invention

[0004] The main objective of this invention is to provide a dexmedetomidine hydrochloride injection solution and its preparation process. The prepared dexmedetomidine hydrochloride injection solution has stable quality, good long-term storage stability, and a simple preparation process that is easy for industrial production.

[0005] This invention provides a dexmedetomidine hydrochloride injection solution, the injection solution comprising dexmedetomidine hydrochloride, sodium chloride, a metal ion chelating agent, a stabilizer, and water for injection.

[0006] The dexmedetomidine hydrochloride injection solution comprises, by mass concentration: 0.005%-0.02% dexmedetomidine hydrochloride, 0.7%-1.1% sodium chloride, 0.5%-5% metal ion chelating agent, 0.05%-0.5% stabilizer, and the balance being water for injection.

[0007] Preferably, the dexmedetomidine hydrochloride injection comprises, by mass concentration: 0.01% dexmedetomidine hydrochloride, 0.8%-1.0% sodium chloride, 1%-3% metal ion chelating agent, 0.05%-0.25% stabilizer, and the balance being water for injection.

[0008] More preferably, the dexmedetomidine hydrochloride injection solution comprises, by mass concentration: 0.01% dexmedetomidine hydrochloride, 0.9% sodium chloride, 2% metal ion chelating agent, 0.15% stabilizer, and the balance being water for injection.

[0009] Preferably, the metal ion chelating agent is selected from one or more of EDTA, sodium gluconate, sodium tartrate, and sodium citrate. More preferably, the metal ion chelating agent is selected from sodium gluconate.

[0010] Preferably, the stabilizer is selected from one or more of SDS, Tween-20, Tween-80, and polyethylene glycol. More preferably, the stabilizer is selected from Tween-80.

[0011] This invention also provides a method for preparing dexmedetomidine hydrochloride injection, comprising the following steps: adding an appropriate amount of water for injection to a mixing tank and introducing an inert gas; weighing the prescribed amounts of sodium chloride, metal ion chelating agent, and stabilizer, adding them to the water for injection, stirring to dissolve, then adding the prescribed amounts of dexmedetomidine hydrochloride, stirring to dissolve, and bringing the volume to a final volume with water for injection; filtering the solution, filling, filling with nitrogen, stoppering, and capping; and terminally sterilizing the capped solution to obtain the final product.

[0012] Furthermore, the inert gas is selected from nitrogen.

[0013] Furthermore, the drug solution is filtered through 0.45μm and 0.22μm microporous membranes, respectively.

[0014] Furthermore, the moist heat sterilization parameters are 121°C for 15 minutes.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: by adding metal ion chelating agents and stabilizers and screening their types, the present invention optimizes the preparation process of the injection solution, and the dexmedetomidine hydrochloride injection solution prepared by the present invention does not darken in color, has stable pH and stable related substances during long-term storage, and has good stability. Moreover, the preparation process is simple and easy to operate, and is easy to industrialize. Detailed Implementation

[0016] In view of the deficiencies of the prior art, the inventors, through long-term research and extensive practice, have proposed the technical solution of this invention. The invention is further illustrated below by means of embodiments, but these embodiments do not constitute a limitation of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0017] Example 1: Addition and Screening of Metal Ion Chelating Agents

[0018] Name of raw materials Prescription 1 Prescription 2 Prescription 3 Prescription 4 Dexmedetomidine hydrochloride 0.01％ 0.01％ 0.01％ 0.01％ Sodium chloride 0.9％ 0.9％ 0.9％ 0.9％ EDTA \ 2％％ \ \ Sodium gluconate \ \ 2％％ \ Sodium tartrate \ \ \ 2％％ Twain-80 0.15％ 0.15％ 0.15％ 0.15％ Water for injection margin margin margin margin

[0019] Preparation method: Add 80% water for injection to the mixing tank and purge with nitrogen; weigh out the prescribed amounts of sodium chloride, metal ion chelating agent, and stabilizer, add them to the water for injection, stir and dissolve, then add the prescribed amount of dexmedetomidine hydrochloride, stir and dissolve, and bring the volume up with water for injection; filter the drug solution through 0.45μm and 0.22μm microporous membranes respectively, fill, fill with nitrogen, stopper, crimp cap, and sterilize by moist heat at 121℃ for 15min to obtain the final product.

[0020] The injection samples were placed at 60℃ for 10 days and under 4500lx light for 10 days to investigate the effects of temperature and light on the properties, pH, content, and related substances of the injection. The results are shown in the table below.

[0021]

[0022] The results in the table above show that when Tween-80 is used as a stabilizer, the injection prepared in Formula 1 without the addition of a metal ion chelating agent darkens and turns yellowish in color, decreases in content, and increases in related substances after 10 days of exposure to light and high temperature. When EDTA and sodium tartrate are used as metal ion chelating agents, the injection prepared in Formula 3 darkens and turns yellowish in color, decreases in content, and increases in related substances after 10 days of exposure to light. After 10 days of exposure to high temperature, the color does not darken and turns yellow, but the content decreases and related substances increase. Formula 3, using sodium gluconate as a metal ion chelating agent, does not change color after 10 days of exposure to light and high temperature, and the pH, content, and related substances are relatively stable, indicating stable quality.

[0023] Example 2: Stabilizer Addition and Type Screening

[0024]

[0025] The preparation method is the same as in Example 1.

[0026] The injection samples were placed at 60℃ for 10 days and under 4500lx light for 10 days to investigate the effects of temperature and light on the properties, pH, content, and related substances of the injection. The results are shown in the table below.

[0027]

[0028]

[0029] The results in the table above show that when sodium gluconate is used as a metal ion chelating agent, without the addition of a stabilizer, and when SDS, Tween-20, or polyethylene glycol are used as stabilizers, the prepared injection solution, after being placed under light for 10 days, will darken in color to yellow, decrease in content, and increase in related substances. After being placed under high temperature for 10 days, the color will not darken to yellow, but the content will decrease, and related substances will increase. Formula 3, using Tween-80 as a stabilizer, prepared an injection solution that did not change color after being placed under both light and high temperature for 10 days, and the pH, content, and related substances were relatively stable, indicating stable quality.

[0030] Example 3: Optimization of Preparation Process

[0031] Formula 9 and Formula 3 have identical formulations, but differ in their preparation methods, which are as follows:

[0032] Add 80% water for injection to the mixing tank and purge with nitrogen; weigh out the prescribed amounts of sodium chloride and dexmedetomidine hydrochloride, stir to dissolve, then add the metal ion chelating agent and stabilizer, stir to dissolve, and bring to volume with water for injection; filter the solution through 0.45μm and 0.22μm microporous membranes respectively, fill, fill with nitrogen, stopper, crimp cap, and sterilize at 121℃ for 15 minutes to obtain the final product.

[0033] The injection samples were placed at 60℃ for 10 days and under 4500lx light for 10 days to investigate the effects of temperature and light on the properties, pH, content, and related substances of the injection. The results are shown in the table below.

[0034]

[0035] The results in the table above show that when dexmedetomidine hydrochloride is added first and then dissolved by stirring, followed by the addition of the metal ion chelating agent and stabilizer, the prepared injection solution, after being exposed to light and high temperature for 10 days, will darken in color to yellow, decrease in content, and increase in related substances. Therefore, during the preparation process, the metal ion chelating agent and stabilizer should be added first and then dissolved by stirring before adding dexmedetomidine hydrochloride. In other words, during the solution preparation process, dexmedetomidine hydrochloride should be added only when the metal ion chelating agent and stabilizer are dissolved.

[0036] Example 4 Stability Study

[0037] The dexmedetomidine hydrochloride injection prepared according to Formula 3 was subjected to accelerated stability testing at 40℃ / 75% RH and long-term stability testing at 25℃ / 60% RH. The results are as follows:

[0038]

[0039] The results in the table above show that using sodium gluconate as a metal ion chelating agent and Tween-80 as a stabilizer, and adding dexmedetomidine hydrochloride for dissolution in the presence of the metal ion chelating agent and stabilizer during the solution preparation process, the prepared injection solution did not change color after being placed for 6 months and 24 months under accelerated stability and long-term stability test conditions, respectively. Moreover, the pH, content and related substances were relatively stable, indicating good stability and long-term storage.

[0040] It should be understood that the technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made to the technical solutions of the present invention without departing from the spirit and scope of the claims are within the scope of protection of the present invention.

Claims

1. A dexmedetomidine hydrochloride injection solution, characterized in that, The injection solution comprises dexmedetomidine hydrochloride, sodium chloride, a metal ion chelating agent, a stabilizer, and water for injection. The metal ion chelating agent is sodium gluconate, and the stabilizer is Tween-80. The preparation method of the dexmedetomidine hydrochloride injection solution includes the following steps: adding an appropriate amount of water for injection to a mixing tank, introducing an inert gas, weighing the prescribed amounts of sodium chloride, metal ion chelating agent, and stabilizer, adding them to the water for injection, stirring to dissolve, then adding the prescribed amount of dexmedetomidine hydrochloride, stirring to dissolve, making up the volume with water for injection, filtering the solution, filling, filling with nitrogen, stoppering, capping, and terminal sterilizing to obtain the final product.

2. The dexmedetomidine hydrochloride injection according to claim 1, characterized in that, The dexmedetomidine hydrochloride injection solution comprises, by mass concentration: 0.005%-0.02% dexmedetomidine hydrochloride, 0.7%-1.1% sodium chloride, 0.5%-5% metal ion chelating agent, 0.05%-0.5% stabilizer, and the balance being water for injection.

3. The dexmedetomidine hydrochloride injection according to claim 2, characterized in that, The dexmedetomidine hydrochloride injection solution comprises, by mass concentration: 0.01% dexmedetomidine hydrochloride, 0.8%-1.0% sodium chloride, 1%-3% metal ion chelating agent, 0.05%-0.25% stabilizer, and the balance being water for injection.

4. The dexmedetomidine hydrochloride injection according to claim 3, characterized in that, The dexmedetomidine hydrochloride injection solution comprises, by mass concentration: 0.01% dexmedetomidine hydrochloride, 0.9% sodium chloride, 2% metal ion chelating agent, 0.15% stabilizer, and the balance being water for injection.

5. A method for preparing dexmedetomidine hydrochloride injection, characterized in that, The preparation method includes the following steps: adding an appropriate amount of water for injection to a mixing tank, introducing an inert gas, weighing the prescribed amounts of sodium chloride, metal ion chelating agent, and stabilizer, adding them to the water for injection, stirring to dissolve, then adding the prescribed amount of dexmedetomidine hydrochloride, stirring to dissolve, making up to volume with water for injection, filtering the solution, filling, filling with nitrogen, stoppering, crimping, and terminal sterilizing to obtain the final product; the metal ion chelating agent is sodium gluconate, and the stabilizer is Tween-80.

6. The method for preparing dexmedetomidine hydrochloride injection according to claim 5, characterized in that, The inert gas is nitrogen.

7. The method for preparing dexmedetomidine hydrochloride injection according to claim 6, characterized in that, The drug solution was filtered through 0.45μm and 0.22μm microporous membranes, respectively.

8. The method for preparing dexmedetomidine hydrochloride injection according to claim 7, characterized in that, The sterilization parameters are 121℃ and 15min.

9. The method for preparing dexmedetomidine hydrochloride injection according to any one of claims 5-8, characterized in that, The prepared dexmedetomidine hydrochloride injection solution comprises, by mass concentration: 0.01% dexmedetomidine hydrochloride, 0.8%-1.0% sodium chloride, 1%-3% metal ion chelating agent, 0.05%-0.25% stabilizer, and the balance being water for injection.

10. The method for preparing dexmedetomidine hydrochloride injection according to claim 9, characterized in that, The prepared dexmedetomidine hydrochloride injection solution comprises, by mass concentration: 0.01% dexmedetomidine hydrochloride, 0.9% sodium chloride, 2% metal ion chelating agent, 0.15% stabilizer, and the balance being water for injection.

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