Dexmedetomidine and propofol combined reagent and combination method

Abstract

The invention discloses a dexmedetomidine and propofol combined reagent and a combination method, and relates to the technical field of combined use of anesthetic drugs. According to the method, firstly, dexmedetomidine is subjected to intravenous pump injection within 5-15 minutes according to the dosage of 0.5-1.0 mu g / kg, propofol is given within 2 minutes after the dexmedetomidine is subjected to general anesthesia, and the dosage of the propofol can be reduced by 10%-50% compared with that of propofol which is independently used. Through pretreatment of dexmedetomidine, the anesthetic effect of propofol can be enhanced, adverse reactions such as blood pressure drop and respiratory depression can be effectively reduced, and anesthetic safety and controllability are improved. The combined reagent comprises independent containers for respectively loading the dexmedetomidine injection and the propofol emulsion, and can be packaged by adopting a double-cavity pre-filled injector, and sequential injection is realized through a controllable opening mechanism, so that unstable emulsification and titer change caused by physical mixing of medicines are avoided.

Description

Technical Field

[0001] The present invention relates to the technical field of combined use of anesthetic drugs, and in particular to a combination agent of dexmedetomidine and propofol and a combined use method. Background Art

[0002] Propofol is a short-acting intravenous anesthetic commonly used for induction and maintenance of clinical anesthesia. It has the characteristics of rapid onset, short duration of action, and fast recovery. It is widely used in various medical scenarios that require rapid onset and short-term general anesthesia, such as outpatient surgery, day anesthesia, and modified electroconvulsive therapy. In order to achieve a rapid and sufficient anesthetic effect, a certain dose of propofol is usually administered clinically based on the patient's weight and individual differences. However, propofol has dose-dependent side effects, including decreased blood pressure, slowed heart rate, and respiratory depression, which are especially pronounced when injected intravenously at high doses. Therefore, in actual operations, anesthesiologists need to closely monitor the patient's circulation and respiratory conditions while ensuring the depth of anesthesia to prevent adverse reactions.

[0003] Dexmedetomidine is a highly selective α2-adrenergic receptor agonist with sedative, analgesic, and anxiolytic effects. It is commonly used for sedation management in critical care and intraoperative or postoperative sedation. Dexmedetomidine is administered via intravenous infusion, has a relatively smooth onset of action, and has minimal effects on the respiratory system. It can maintain sedation while reducing the frequency of sedative medication use. Its sedative effect can be monitored using methods such as electroencephalography (EEG) or the bispectral index, allowing for dose adjustments as needed during treatment. Due to its slow onset of action, dexmedetomidine is typically administered in advance of anticipated sedation or anesthesia needs, with controlled infusion rate and concentration to avoid adverse reactions such as blood pressure fluctuations or bradycardia caused by overly rapid administration.

[0004] In actual clinical applications, propofol and dexmedetomidine are used in different types of anesthesia induction and sedation scenarios, respectively. However, there is still a certain degree of variability in their specific usage, dosage selection, medication sequence, monitoring methods, etc., and the lack of unified parameter settings and standardized processes brings certain uncertainties to clinical operations and may also affect the safety and effectiveness of medication. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the present invention aims to provide a method for the combined use of dexmedetomidine and propofol and a combined reagent.

[0006] The above-mentioned object of the present invention is achieved through the following technical solutions: A method for the combined use of dexmedetomidine and propofol comprises the following steps: The combined use is used in drugs for rapid induction and short-term general anesthesia, comprising the following steps: Before general anesthesia, dexmedetomidine was administered intravenously at a dose of 0.5–1.0 μg / kg over 5–15 minutes. Propofol was administered within 2 minutes after the completion of dexmedetomidine administration; Among them, the dosage of propofol was reduced by 10% to 50% compared with that without dexmedetomidine pretreatment. Dexmedetomidine was dissolved in normal saline to a concentration of 4 μg / mL and infused at a rate of 0.05-0.1 μg / kg per minute; propofol was a 1% milky white oil-in-water emulsion; both were administered through independent infusion routes, and the total intravenous fluid infusion rate did not exceed 10 mL / min.

[0007] Furthermore, the dosage of dexmedetomidine is 0.7 μg / kg, and the intravenous infusion time is 10 minutes.

[0008] Furthermore, it is characterized in that the propofol is administered by rapid intravenous injection, and the injection dose is 1.0 to 2.0 mg / kg.

[0009] Furthermore, it is characterized in that the method is used in medical scenarios requiring rapid induction and short-term general anesthesia.

[0010] Furthermore, it is characterized in that the depth of anesthesia of the subject is monitored after the administration of propofol, and the monitoring method is bispectral index (BIS) or electroencephalogram (EEG) monitoring.

[0011] This combination therapy involves inducing anesthesia by administering dexmedetomidine at a dose of 0.5 to 1.0 μg / kg intravenously before general anesthesia and administering propofol within 2 minutes of injection. The key to this approach is that dexmedetomidine, as a premedication, significantly enhances the anesthetic effect of propofol, thereby reducing the actual propofol dosage by 10% to 50% without compromising the depth and quality of anesthesia. This synergistic effect not only helps reduce the risks of propofol use (such as hypotension, respiratory depression, and cognitive impairment), but also delays the development of drug resistance, improving safety and clinical controllability. Dexmedetomidine, by activating central α2-adrenergic receptors, exhibits significant sedative, anxiolytic, and circulatory stabilizing effects. Its combination with propofol demonstrates a clear pharmacological synergy. Electroencephalographic (EEG) monitoring also demonstrates that Dex enhances the deep anesthesia induced by propofol, as demonstrated by decreased BIS values and enhanced EEG delta waves, further supporting the feasibility of efficacy enhancement and dose reduction.

[0012] A dexmedetomidine and propofol combination reagent, comprising: An injection solution containing dexmedetomidine dissolved in normal saline at a concentration of 4 μg / mL; A milky white water-in-oil emulsion containing 1% propofol; The dexmedetomidine and propofol are respectively packaged in separate containers and equipped with separate infusion devices, and are configured for the combined use method according to any one of claims 1 to 5.

[0013] Furthermore, the dexmedetomidine injection is used for intravenous infusion at a rate of 0.05 to 0.1 μg / kg per minute, with a dosage range of 0.5 to 1.0 μg / kg and an injection time of 5 to 15 minutes.

[0014] Furthermore, the dexmedetomidine injection and propofol emulsion are respectively encapsulated in a double-chamber prefilled syringe, which includes a first cavity and a second cavity, respectively storing dexmedetomidine and propofol. The syringe is equipped with a controllable opening mechanism, which can enable the first cavity and the second cavity to release the contents in sequence according to a set order and is suitable for sequential infusion operations.

[0015] Furthermore, the dexmedetomidine injection contains an antioxidant, a chelating agent and a pH buffer system, wherein the antioxidant is sodium bisulfite, the chelating agent is disodium edetate, and the pH buffer system is an acetate buffer, which is used to improve the stability of the preparation during storage, and the target pH range is 4.8 to 5.5.

[0016] Furthermore, the combined reagent includes a set of two-component combination preparations for use in combination, namely: The first component is dexmedetomidine injection, which contains dexmedetomidine, a pH buffer system (pH 4.8-5.5), sodium bisulfite as an antioxidant, and polysorbate 80 as a surfactant to maintain the physical stability of the low-concentration solution; The second component is a propofol emulsion, which contains propofol, refined soybean oil, medium-chain triglycerides, lecithin, and glycerol, and is chelated with Na2EDTA to inhibit emulsion instability caused by metal ions; The first component and the second component are administered intravenously in sequence, with the infusion interval controlled to no more than 2 minutes, and independent infusion pathways are required to avoid physical mixing; When dexmedetomidine and propofol are infused sequentially intravenously with an interval of no more than 2 minutes, the combined preparation can maintain a content change of ≤±5% and an average particle size change of ≤±10% for at least 30 minutes.

[0017] This invention proposes encapsulating dexmedetomidine injection and propofol emulsion separately in a dual-chamber prefilled syringe equipped with a controllable opening mechanism for sequential release, demonstrating its high degree of innovation and ease of use. Traditionally, dexmedetomidine and propofol must be administered through separate channels, increasing operational complexity and the risk of cross-contamination and misuse. Through structural integration and mechanism design, the dual-chamber prefilled syringe enables precise sequential infusion of the two drugs at set intervals. This design is particularly well-suited for the "sequential infusion within 2 minutes" strategy proposed in this invention, effectively avoiding emulsion instability and biocompatibility issues associated with physical mixing of the drugs. Furthermore, this injection device is particularly suitable for fast-paced emergency and preoperative settings, offering irreplaceable technical advantages in improving operational efficiency and reducing human intervention errors. Its design also considers drug stability requirements. For example, a buffer system, antioxidants, and surfactants are incorporated into dexmedetomidine to effectively maintain its chemical stability and solution homogeneity, ensuring its efficacy over a long storage period and meeting clinical infusion accuracy and batch consistency requirements.

[0018] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in the following aspects: 1. The pretreatment effect of dexmedetomidine significantly reduces the dosage of propofol, effectively reduces the incidence of adverse reactions such as cardiovascular depression and postoperative delirium, and improves anesthesia safety.

[0019] 2. Research based on the central nervous system electrophysiological mechanism has verified that dexmedetomidine can enhance the depth of anesthesia induced by propofol, which is manifested by an increase in the delta wave and a decrease in the BIS value in the electroencephalogram, ensuring the scientificity and controllability of the combined effect.

[0020] 3. Antioxidants, chelating agents and buffer systems are added to the preparation formula to significantly improve the stability of dexmedetomidine preparations during storage.

[0021] 4. This method is suitable for various clinical scenarios such as rapid induction, short-term surgery, and electroconvulsive therapy, and has good scalability and practical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Schematic diagram of the double-chamber prefilled syringe in Example 4 of the present invention.

[0023] Description of the accompanying drawings: 1. Controllable opening mechanism. DETAILED DESCRIPTION

[0024] The present invention is described in detail below with reference to the embodiments.

[0025] Example 1: Preparation of Dexmedetomidine Injection 1. Raw materials: Dexmedetomidine base API; Normal saline (0.9% NaCl); Antioxidant: Sodium bisulfite; Chelating agent: disodium ethylenediaminetetraacetic acid (Na2EDTA); pH buffer system: acetate buffer (target pH range 4.8-5.5); Surfactant (when selected): such as Polysorbate 80, etc.

[0026] 2. Formula (taking the preparation of 1000mL injection as an example): Dexmedetomidine base converted to dexmedetomidine content: 4 mg (made into a concentration of 4 μg / mL); Sodium bisulfite: 0.5g; Na2EDTA: 0.2g; Acetate buffer (adjust the solution pH to 4.8-5.5); The balance was made up to 1000 mL with 0.9% NaCl; 0.02% to 0.1% polysorbate 80 was added to improve solution uniformity and physical stability at low concentrations.

[0027] 3. Preparation steps: a) Place an appropriate amount of acetate buffer in a stainless steel stirring vessel and start stirring; b) adding sodium bisulfite and Na2EDTA in sequence, and after they are fully dissolved, adding the dissolved dexmedetomidine raw material; c) Fill the volume to approximately 1000 mL with normal saline (0.9% NaCl), check the pH, and adjust it slightly with acetic acid or sodium acetate solution to keep the final pH of the solution between 4.8 and 5.5. d) If a surfactant (polysorbate 80) is needed, add it before the solution volume is fully replenished and stir evenly; e) Make up the final volume to 1000 mL, filter sterilize (e.g., with a 0.22 μm filter membrane), dispense into ampoules or vials, and package under strict aseptic conditions; f) Store at 2-8°C away from light and regularly check the active ingredient content and appearance.

[0028] When used, this preparation can be administered intravenously using an infusion pump at a set rate (e.g., 0.05-0.1 μg / kg per minute) according to actual clinical needs. It is recommended to complete the pump infusion of a total dose of 0.5-1.0 μg / kg within 5-15 minutes.

[0029] Example 2: Preparation of Propofol Emulsion 1. Raw materials: Propofol API; refined soybean oil; Medium-chain triglycerides (MCT); Lecithin; Glycerol; Na2EDTA (chelation treatment to inhibit emulsion instability caused by metal ions); Water for injection (in accordance with pharmacopoeia).

[0030] 2. Formulation (taking the preparation of 1000 mL of 1% propofol milky white water-in-oil emulsion as an example): Propofol: 10 g (1% of the total emulsion); Refined soybean oil: 100g (may be fine-tuned according to emulsification properties); Medium chain triglycerides: 50g; Lecithin: 12g; Glycerol: 20g; Na2EDTA: 0.5g; The balance was made up to 1000 mL with water for injection.

[0031] 3. Preparation steps: a) Prepare the oil phase: Add refined soybean oil, medium-chain triglycerides, and lecithin in sequence under stirring and mix thoroughly; a) dissolving or dispersing propofol in the oil phase while stirring; b) Prepare the aqueous phase: dissolve glycerol and Na2EDTA in an appropriate amount of water for injection; c) In a homogenizer or high shear emulsifier, slowly add the water phase to the oil phase, maintain a constant temperature (e.g., 25-30°C), and continue emulsifying until a uniform milky white liquid is formed; d) Fill the volume to 1000 mL with water for injection and homogenize the mixture under high pressure (e.g., 6,000-8,000 psi) several times to ensure stable droplet size. e) The final emulsion is aseptically filled into glass bottles or special containers, and tested for appearance, content and average particle size. Once qualified, it is stored at 2-8°C away from light.

[0032] The propofol emulsion is a 1% milky white oil-in-water emulsion, which is usually used for clinical rapid intravenous anesthesia induction or maintenance. The push dose can be in the range of 1.0 to 2.0 mg / kg and can be adjusted according to the pathological condition or experimental needs.

[0033] Example 3: Animal anesthesia experiment using dexmedetomidine combined with propofol 1. Experimental subjects: Healthy rabbits (either sex) weighing 2.0-2.5 kg were selected, with 10 rabbits in each group.

[0034] 2. Grouping and processing: Control group (propofol alone): First, 2 mL of normal saline was administered via intravenous pump (completed within 10 minutes), followed by a single rapid injection of propofol emulsion within 2 minutes, with the dose set at 2.0 mg / kg.

[0035] Experimental group (combination scheme of the present invention): Dexmedetomidine injection (4 μg / mL) was administered intravenously at a rate of 0.07 μg / kg·min for 10 minutes, for a total dose of approximately 0.7 μg / kg; Within 2 minutes after the completion of the dexmedetomidine infusion, a 1.5 mg / kg propofol emulsion was rapidly injected (approximately 25% less than the control group); The total fluid infusion rate was maintained at no more than 10 mL / min throughout the entire process, and dexmedetomidine and propofol were infused through independent pathways to avoid physical mixing.

[0036] 3. Anesthesia depth monitoring: (1) Use an animal electroencephalogram (EEG) or bispectral index (BIS) monitor to record real-time data from rabbits; (2) Record the BIS value or EEG main band 1 minute, 3 minutes, and 5 minutes after the completion of propofol injection to observe the changes in anesthesia depth; (3) Simultaneously monitor the rabbits' heart rate (HR), mean arterial pressure (MAP) and respiratory rate (RR), and record adverse reactions.

[0037] 4. Observation of results: Control group: Anesthesia took effect quickly, but after a bolus injection of 2.0 mg / kg propofol, about 40% of the rabbits experienced transient respiratory depression and a significantly slower heart rate; The BIS value dropped below 50 1 minute after administration and remained so for about 6 to 8 minutes, during which time some rabbits developed low blood pressure.

[0038] Experimental group: During dexmedetomidine pretreatment, rabbits showed mild sedation and stable breathing; When the propofol dose was reduced to 1.5 mg / kg, the BIS value could still be reduced to below 50 within 1 minute and maintained for about 6 minutes. There was no significant difference in the depth and duration of anesthesia compared with the control group. The incidence of adverse reactions has been significantly reduced, such as smaller heart rate fluctuations, less respiratory depression, and more stable blood pressure.

[0039] Conclusion: In an animal model, administering dexmedetomidine (0.7 μg / kg, 10-minute infusion) followed by a rapid bolus of propofol (1.5 mg / kg) achieved a similar depth and duration of anesthesia as 2.0 mg / kg propofol alone, while achieving more stable circulatory and respiratory systems and less respiratory depression. This result supports the proposed technical solution and safety advantages of dexmedetomidine pretreatment, which can reduce propofol dosage by 10% to 50%.

[0040] Example 4: Dual-chamber prefilled syringe packaging and stability testing 1. The structure of double-chamber prefilled syringe is as follows Figure 1 As shown: The first cavity (cavity A, Figure 1 A in the middle indicates the position): Encapsulated dexmedetomidine injection (concentration 4μg / mL, containing appropriate amount of antioxidant and buffer system), capacity 10mL; The second cavity (cavity B, Figure 1 B in the middle indicates the position): Encapsulated propofol emulsion (1% concentration), capacity 10mL; The controllable opening mechanism 1 can be any mechanism that can block and open the flow of cavity A and cavity B. In this embodiment, a clamp is used. By opening the clamp, the solution in cavity A is first released, and then the clamp is clamped back to its original position. Then, the clamp of cavity B is opened at an interval of no more than 2 minutes to release the solution in cavity B, ensuring that the two components are used in sequence and are not mixed.

[0041] 2. Usage simulation: a) Take 10 double-chamber prefilled syringes and simulate rapid anesthesia induction: b) Open chamber A and administer dexmedetomidine at a constant rate over 10 minutes, with a total dose of approximately 0.7 μg / kg (based on a simulated animal weighing 2.5 kg or converted to clinical weight); c) Within 2 minutes after the infusion of the liquid in chamber A is completed, open chamber B and quickly inject propofol.

[0042] d) Observe the two components throughout the process to see if there is any visible turbidity, flocculation or emulsification destruction.

[0043] 3. Storage stability test: a) Store the double-chamber prefilled syringe at 2-8°C in the dark for 0, 7, 15, and 30 days. Randomly sample each time point and test: b) Changes in dexmedetomidine content (HPLC or UPLC method); c) propofol average particle size (measured by laser particle size analyzer) and content; d) Appearance (whether there is stratification, precipitation, or flocculence).

[0044] The results showed that under the above-mentioned anti-oxidation and chelation treatment formulation conditions, the dexmedetomidine content changed by ≤±3%, the propofol content changed by ≤±5%, and the average particle size changed by ≤±8% within 30 days. There was no visible stratification or aggregation, indicating that the preparation had good short-term stability.

[0045] Conclusion: The use of a dual-chamber prefilled syringe effectively prevents physical mixing or emulsification of dexmedetomidine and propofol prior to infusion, maintaining the stability and efficacy of both formulations. Furthermore, the controlled opening mechanism ensures precise sequence execution, meeting the technical requirement of "dexmedetomidine infusion first, followed by propofol injection within 2 minutes" of the present invention, making it particularly suitable for rapid induction surgery and emergency scenarios.

[0046] The above description is merely a preferred embodiment of the present invention. The scope of protection of the present invention is not limited to the above embodiment. All technical solutions based on the concept of the present invention are within the scope of protection of the present invention. It should be noted that for those skilled in the art, various improvements and modifications that do not depart from the principles of the present invention should also be considered within the scope of protection of the present invention.

Claims

1. A method for the combined use of dexmedetomidine and propofol, characterized in that: The combined use is used in drugs for rapid induction and short-term general anesthesia, comprising the following steps: Before general anesthesia, dexmedetomidine was administered intravenously at a dose of 0.5–1.0 μg / kg over 5–15 minutes. Propofol was administered within 2 minutes after the completion of dexmedetomidine administration; Among them, the dosage of propofol was reduced by 10% to 50% compared with that without dexmedetomidine pretreatment. Dexmedetomidine was dissolved in normal saline to a concentration of 4 μg / mL and infused at a rate of 0.05-0.1 μg / kg per minute; propofol was a 1% milky white oil-in-water emulsion; both were administered through independent infusion routes, and the total intravenous fluid infusion rate did not exceed 10 mL / min.

2. The method for combined use of dexmedetomidine and propofol according to claim 1, wherein: The dosage of dexmedetomidine was 0.7 μg / kg, and the intravenous infusion time was 10 minutes.

3. The combined use method of dexmedetomidine and propofol according to claim 1, characterized in that: The propofol is administered by rapid intravenous injection, with a dosage of 1.0 to 2.0 mg / kg.

4. The combined use method of dexmedetomidine and propofol according to claim 1, characterized in that: This method is used in medical scenarios requiring rapid induction and a short duration of general anesthesia.

5. The method for combined use of dexmedetomidine and propofol according to claim 1, characterized in that: After the administration of propofol, the depth of anesthesia of the subjects was monitored by bispectral index (BIS) or electroencephalogram (EEG) monitoring.

6. A reagent for the combined use of dexmedetomidine and propofol according to any one of claims 1 to 5, characterized in that: include: An injection solution containing dexmedetomidine dissolved in normal saline at a concentration of 4 μg / mL; A water-in-oil emulsion containing 1 wt% propofol; The dexmedetomidine and propofol are respectively packaged in independent containers and provided with independent infusion devices.

7. The dexmedetomidine and propofol combined reagent according to claim 6, characterized in that: The dexmedetomidine injection is used for intravenous infusion at a rate of 0.05 to 0.1 μg / kg per minute, with a dosage range of 0.5 to 1.0 μg / kg and an injection time of 5 to 15 minutes.

8. The dexmedetomidine and propofol combined reagent according to claim 6, characterized in that: The dexmedetomidine injection and propofol emulsion are respectively encapsulated in a double-chamber prefilled syringe, which includes a first cavity and a second cavity, respectively storing dexmedetomidine and propofol. The syringe is equipped with a controllable opening mechanism, which can enable the first cavity and the second cavity to release the contents in sequence according to a set order and is suitable for sequential infusion operations.

9. The dexmedetomidine and propofol combined reagent according to claim 6, characterized in that: The dexmedetomidine injection contains an antioxidant, a chelating agent and a pH buffer system, wherein the antioxidant is sodium bisulfite, the chelating agent is disodium ethylenediaminetetraacetic acid, and the pH buffer system is an acetate buffer solution, and the pH range is controlled to be 4.8 to 5.

5.

10. The dexmedetomidine and propofol combined reagent according to claim 6, characterized in that: The combined reagent includes a set of two-component combination preparations for use in combination, namely: The first component is dexmedetomidine injection, which contains dexmedetomidine, a pH buffer system (pH 4.8-5.5), sodium bisulfite as an antioxidant, and polysorbate 80 as a surfactant; The second component is a propofol emulsion containing propofol, refined soybean oil, medium-chain triglycerides, lecithin, and glycerol, and is chelated with Na2EDTA; The first component and the second component are intravenously infused in sequence, and the infusion interval is controlled to no more than 2 minutes; When dexmedetomidine and propofol are infused sequentially intravenously with an interval of no more than 2 minutes, the combined preparation can maintain a content change of ≤±5% and an average particle size change of ≤±10% for at least 30 minutes.

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