Dexmedetomidine hydrochloride injection and preparation process thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a dexmedetomidine hydrochloride injection and a preparation process thereof. 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. According to the dexmedetomidine hydrochloride injection, the metal ion chelating agent and the stabilizer are added, the types of the metal ion chelating agent and the stabilizer are screened, the preparation process of the injection is optimized, the prepared dexmedetomidine hydrochloride injection does not discolor in the long-term storage and placement process, the pH is stable, related substances are stable, the dexmedetomidine hydrochloride injection has good stability, the preparation process is simple and easy to operate, and industrial production is easy.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a dexmedetomidine hydrochloride injection and a preparation process thereof. Background Art

[0002] Dexmedetomidine hydrochloride is an α2-adrenaline receptor agonist, and its chemical name is: (+)-4-(S)-1-(2,3-dimethylphenyl)ethyl-1H-imidazole hydrochloride. α2-adrenaline receptors are widely present in the central nervous system, peripheral nerves, and autonomic ganglia. Studies have shown that the excitation of presynaptic α2-adrenaline receptors located at the sympathetic nerve endings can inhibit the release of norepinephrine. α2 agonists in the central nervous system can activate postsynaptic receptors, reduce sympathetic activity, and thus reduce blood pressure and heart rate. Reduced sympathetic nerve outflow can lead to a reduction in the need for anesthetics. Dexmedetomidine hydrochloride has unique advantages over other sedatives. It is 7 to 8 times more effective than clonidine. It has strong pharmacological effects such as sedation, analgesia, antianxiety, and inhibition of sympathetic nerve activity. It also has the characteristics of intraoperative awakening, no respiratory depression, and stable perioperative hemodynamics. At the same time, it can significantly reduce side effects such as postoperative chills, nausea and vomiting. Currently, dexmedetomidine hydrochloride injection on the market is available in small volume injections of 1 ml and 2 ml.

[0003] However, the dexmedetomidine hydrochloride drug itself is easily affected by light and metal ions. The injection is prone to problems such as darkening of color, unstable pH, and increase of related substances during storage. Its poor stability brings certain difficulties to large-scale production. How to screen suitable formulation prescriptions and optimize the preparation process to ultimately ensure that the dexmedetomidine hydrochloride injection will not change color, maintain stable pH, and maintain stable related substances and product quality during long-term storage is an urgent problem that pharmaceutical manufacturers need to solve. Summary of the invention

[0004] The main purpose of the present invention is to provide a dexmedetomidine hydrochloride injection and a preparation process thereof. The prepared dexmedetomidine hydrochloride injection has stable quality, good long-term storage stability, simple preparation process and is easy for industrial production.

[0005] The invention provides a dexmedetomidine hydrochloride injection, which comprises dexmedetomidine hydrochloride, sodium chloride, a metal ion chelating agent, a stabilizer and water for injection.

[0006] The dexmedetomidine hydrochloride injection 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 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 water for injection.

[0008] More preferably, the dexmedetomidine hydrochloride injection comprises, by mass concentration, 0.01% dexmedetomidine hydrochloride, 0.9% sodium chloride, 2% metal ion chelating agent, 0.15% stabilizer, and the balance 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] The invention also provides a preparation method of dexmedetomidine hydrochloride injection, comprising the following steps: adding an appropriate amount of water for injection into a liquid preparation tank, and introducing an inert gas; weighing a prescribed amount of sodium chloride, a metal ion chelating agent, and a stabilizer, adding the mixture to the water for injection, stirring and dissolving, and then adding a prescribed amount of dexmedetomidine hydrochloride, stirring and dissolving, and constant volume with water for injection; filtering the liquid medicine, filling, nitrogen filling, plugging, and capping; and terminally sterilizing the liquid medicine after capping to obtain the liquid medicine.

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

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

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

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: the present invention adds a metal ion chelating agent and a stabilizer, screens the types thereof, and optimizes the preparation process of the injection, so that the dexmedetomidine hydrochloride injection prepared by the present invention does not deepen in color, has a stable pH value, and has stable related substances during long-term storage, and has good stability; the preparation process is simple and easy to operate, and is easy to industrialize for production. DETAILED DESCRIPTION

[0016] In view of the defects of the prior art, the inventor has proposed the technical solution of the present invention after long-term research and extensive practice. The present invention is further illustrated by embodiments below, but these embodiments do not constitute a limitation of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0017] Example 1 Addition of metal ion chelating agents and selection of types

[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 into the liquid preparation tank and pass nitrogen; weigh the prescribed amount of sodium chloride, metal ion chelating agent and stabilizer, add them to the water for injection, stir to dissolve, then add the prescribed amount of dexmedetomidine hydrochloride, stir to dissolve, and make up to volume with water for injection; filter the liquid through 0.45μm and 0.22μm microporous filter membranes respectively, fill, fill with nitrogen, press stopper, roll cap, and sterilize with wet heat at 121℃ for 15min to obtain the product.

[0020] The injection samples were placed at 60°C for 10 days and at 4500lx light conditions 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] From the results in the above table, it can be seen that when Tween-80 is used as a stabilizer, no metal ion chelator is added to prescription 1. The prepared injection is placed under light and high temperature conditions for 10 days, and the color will deepen and turn yellow, the content will decrease, and the related substances will increase. When EDTA and sodium tartrate are used as metal ion chelators, the prepared injection is placed under light conditions for 10 days, the color will deepen and turn yellow, the content will decrease, and the related substances will increase. When placed under high temperature conditions for 10 days, the color does not deepen and turn yellow, but the content will decrease, and the related substances will also increase. Prescription 3 uses sodium gluconate as a metal ion chelator. The prepared injection is placed under light and high temperature conditions for 10 days without discoloration, and the pH, content and related substances are relatively stable, and the quality is stable.

[0023] Example 2 Stabilizer addition and type screening

[0024]

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

[0026] The injection samples were placed at 60°C for 10 days and at 4500lx light conditions 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] From the results in the table above, it can be seen that when sodium gluconate is used as a metal ion chelating agent, no stabilizer is added, and SDS, Tween-20 or polyethylene glycol is used as a stabilizer, the prepared injection solution will deepen and turn yellow after being placed under light conditions for 10 days, the content will decrease, and the related substances will increase. When placed under high temperature conditions for 10 days, the color will not deepen and turn yellow, but the content will decrease, and the related substances will also increase. Prescription 3 uses Tween-80 as a stabilizer. The prepared injection solution has not changed color after being placed under light and high temperature conditions for 10 days, and the pH, content and related substances are relatively stable, and the quality is stable.

[0030] Example 3 Preparation process optimization

[0031] The compositions of prescription 9 and prescription 3 are exactly the same, but the preparation methods are different. The preparation methods are as follows:

[0032] Add 80% water for injection into the liquid preparation tank and introduce nitrogen; weigh the prescribed amount of sodium chloride and dexmedetomidine hydrochloride, stir to dissolve, then add metal ion chelator and stabilizer, stir to dissolve, and make up to volume with water for injection; filter the liquid through 0.45μm and 0.22μm microporous filter membranes respectively, fill, charge with nitrogen, plug, cap, and sterilize at 121℃ for 15min.

[0033] The injection samples were placed at 60°C for 10 days and at 4500lx light conditions 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] It can be seen from the results in the above table that after adding dexmedetomidine hydrochloride and stirring to dissolve, the metal ion chelator and stabilizer are added. When the prepared injection is placed under light and high temperature conditions for 10 days, the color will deepen and turn yellow, the content will decrease, and the related substances will increase. Therefore, in the preparation process, the metal ion chelator and stabilizer should be added and dissolved first, and then the dexmedetomidine hydrochloride should be added and stirred to dissolve, that is, in the process of preparing the solution, the dexmedetomidine hydrochloride should be added under the condition that the metal ion chelator and stabilizer are dissolved.

[0036] Example 4 Stability Study

[0037] The dexmedetomidine hydrochloride injection prepared in prescription 3 was subjected to accelerated stability test at 40°C / RH75%, and long-term stability test at 25°C / RH60%. The results are as follows:

[0038]

[0039] From the results in the above table, it can be seen that sodium gluconate is used as a metal ion chelating agent and Tween-80 is used as a stabilizer. During the preparation process, dexmedetomidine hydrochloride is added and stirred to dissolve in the presence of the metal ion chelating agent and the stabilizer. The prepared injection solution was placed for 6 months and 24 months under the conditions of accelerated stability and long-term stability tests, respectively, without discoloration, and the pH, content and related substances are relatively stable, with good stability and can be stored for a long time.

[0040] It should be understood that the technical solution of the present invention is not limited to the above-mentioned specific implementation cases. Any technical deformation made according to the technical solution of the present invention without departing from the scope of protection of the purpose of the present invention and the claims shall fall within the protection scope of the present invention.

Claims

1. A dexmedetomidine hydrochloride injection, characterized in that: The injection comprises dexmedetomidine hydrochloride, sodium chloride, a metal ion chelator, a stabilizer and water for injection, wherein the metal ion chelator is sodium gluconate and the stabilizer is Tween-80. The preparation method of the dexmedetomidine hydrochloride injection comprises the following steps: adding an appropriate amount of water for injection into a liquid preparation tank, introducing an inert gas, weighing a prescribed amount of sodium chloride, a metal ion chelator and a stabilizer, adding the prescribed amount of dexmedetomidine hydrochloride, stirring and dissolving, adding a prescribed amount of dexmedetomidine hydrochloride, stirring and dissolving, making up the volume with water for injection, filtering the liquid medicine, filling, nitrogen filling, plugging, capping, and terminal sterilization to obtain the product.

2. The dexmedetomidine hydrochloride injection according to claim 1, characterized in that: The dexmedetomidine hydrochloride injection 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 water for injection.

3. The dexmedetomidine hydrochloride injection according to claim 2, characterized in that: 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 water for injection.

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

5. A method for preparing dexmedetomidine hydrochloride injection, characterized in that: The preparation method comprises the following steps: adding an appropriate amount of water for injection into a liquid preparation tank, introducing an inert gas, weighing a prescribed amount of sodium chloride, a metal ion chelating agent and a stabilizer, adding the prescribed amount of dexmedetomidine hydrochloride, stirring and dissolving, and then adding the prescribed amount of dexmedetomidine hydrochloride, stirring and dissolving, making up the volume with water for injection, filtering the liquid medicine, filling, nitrogen filling, plugging, capping, and terminal sterilization to obtain the 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 0.45 μm and 0.22 μm microporous filter membranes respectively.

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

9. The method for preparing dexmedetomidine hydrochloride injection according to any one of claims 5 to 8, characterized in that: The prepared 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 water for injection.

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

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