CN116139137A - Sustained-release anesthetic composition and preparation method thereof - Google Patents
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Abstract
The invention discloses a slow-release anesthetic composition and a preparation method thereof, wherein the slow-release anesthetic composition comprises the following components in parts by weight: 10-50 parts of long-acting anesthesia compound, 1-6 parts of emulsifier, 1-15 parts of surfactant, 0.5-2.5 parts of polyoxyethylene fatty alcohol ether and the balance of physiological saline; the long-acting anesthetic compound comprises the following components in parts by weight: 10-50 parts of bupivacaine, 5-35 parts of tricine and 10-30 parts of lipid complex; the invention belongs to the technical field of anesthetic compositions; according to the invention, the local anesthesia duration can be prolonged by adding the bupivacaine, the trimercane and the lipid complex, and the pH of the slow-release anesthetic composition is increased to increase the nonionic free base form, so that the local anesthesia onset time is accelerated, and the polyoxyethylene fatty alcohol ether can enable the bupivacaine and the trimercane to exist stably in the form of hydrochloride, thereby effectively solving the problems of relatively short action time and poor stability of local anesthetics in the current market.
Description
Technical Field
The invention belongs to the technical field of anesthetic compositions, and particularly relates to a slow-release anesthetic composition and a preparation method thereof.
Background
Local anesthetics are drugs capable of blocking the occurrence and conduction of sensory nerve impulses in a local reversible way, play an indispensable role in clinical anesthesia and various acute and chronic pain treatments, but compared with clinical requirements, the existing local anesthetics have relatively short action time and poor stability, and a method for prolonging the action time by repeated administration of an imbedded catheter has certain complications such as catheter blockage, nerve injury, soft spinal film inflammation and the like, so that the development of new long-acting local anesthetics is an aim of many researchers.
Disclosure of Invention
Aiming at the situation, in order to overcome the defects of the prior art, the invention provides the slow-release anesthetic composition and the preparation method thereof, wherein the slow-release anesthetic composition comprises the bupivacaine, the tricaine and the lipid complex, so that the local anesthesia duration time can be prolonged, and meanwhile, the pH of the slow-release anesthetic composition is increased to increase the nonionic free base form, so that the local anesthesia onset time is accelerated, and the polyoxyethylene fatty alcohol ether can enable the bupivacaine and the tricaine to exist stably in the form of hydrochloride, so that the problems of relatively short action time and poor stability of local anesthetics in the current market are effectively solved.
The technical scheme adopted by the invention is as follows: the invention provides a slow-release anesthetic composition and a preparation method thereof, wherein the slow-release anesthetic composition comprises the following components in parts by weight: 10-50 parts of long-acting anesthesia compound, 1-6 parts of emulsifier, 1-15 parts of surfactant, 0.5-2.5 parts of polyoxyethylene fatty alcohol ether and the balance of physiological saline; the long-acting anesthetic compound comprises the following components in parts by weight: 10-50 parts of bupivacaine, 5-35 parts of tricine and 10-30 parts of lipid complex.
Preferably, the long-acting anesthetic complex comprises the following components in parts by weight: 15-35 parts of bupivacaine, 10-25 parts of tricine and 15-25 parts of lipid complex.
Further, the lipid complex comprises the following components in parts by weight: 10-20 parts of 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer and 1-15 parts of phospholipid polyethylene glycol.
Further, the preparation method of the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer comprises the following steps:
(1) 1-ethyl-3-methyl imidazole bromide is dissolved in 0.1mol/L acetic acid solution to prepare solution A, then 10mL of ethanol is dripped into the solution A, and stirring is carried out for 10 minutes at room temperature to prepare solution B;
(2) Dibenzoyl peroxide and methyl methacrylate are added into the solution B, the temperature is 60 ℃, and the reaction time is 2 hours;
(3) Washing with acetone for 3 times, filtering and collecting to prepare the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate grafted copolymer.
Preferably, the mass ratio of the 1-ethyl-3-methyl brominated imidazole to the methyl methacrylate is 1:3-1:5.
Further, the emulsifier comprises one or more of sorbitol monostearate, polyoxyethylated castor oil, and sodium lauryl sulfate.
Further, the surfactant comprises one or more combinations of sodium cholate, stearic acid, lecithin, and fatty acid glyceride.
Further, the physiological saline is sodium chloride solution with the concentration of 0.6-0.9% g/mL.
The invention also provides a preparation method of the slow-release anesthetic composition, which comprises the following steps:
(1) Dissolving 10-20 parts of 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer, 1-15 parts of phospholipid polyethylene glycol, 1-6 parts of emulsifier, 1-15 parts of surfactant and 0.5-2.5 parts of polyoxyethylene fatty alcohol ether in acetone to prepare an oil phase A;
(2) Stirring 15-35 parts of bupivacaine, 10-25 parts of tricine and 0.6-0.9% g/mL of physiological saline until the bupivacaine and the physiological saline are completely dissolved, and preparing a water phase B;
(3) Next, the oil phase a is ultrasonically emulsified in the ice-bath water phase B for 5 minutes to prepare a mixture;
(4) And finally, stirring the mixture obtained in the step (3) for 12 hours at room temperature, evaporating acetone, centrifugally collecting to obtain the slow-release anesthetic composition, and washing with ultrapure water.
Further, the pH of the slow-release anesthetic composition is less than or equal to 8.0.
The beneficial effects obtained by the invention are as follows:
(1) The scheme provides a slow-release anesthetic composition, wherein, the sustained-release anesthetic composition is added with the bupivacaine, the trimercacaine and a lipid compound formed by a 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer and phospholipid polyethylene glycol, so that the duration of local anesthesia can be prolonged and the side effect can be reduced;
(2) The lipid complex formed by the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer and the phospholipid polyethylene glycol can prolong the local anesthesia circulation time, release the medicine at a sustained speed within the optimal medicine concentration range, thereby reducing the toxicity caused by severe fluctuation of the plasma medicine concentration;
(3) Controlling the pH of the slow-release anesthetic composition in the process of preparing the slow-release anesthetic composition, so that the nonionic free base form is increased, and the local anesthetic onset time is accelerated;
(4) The polyoxyethylene fatty alcohol ether added into the slow-release anesthetic composition can enable the bupivacaine and the tricaine to exist stably in the form of hydrochloride, so that the stability of the slow-release anesthetic composition is enhanced;
(5) Compared with other local anesthetics, the bupivacaine and the trimecaine can be rapidly decomposed in vivo, and metabolites are discharged from urine, so that the bupivacaine and the trimecaine can be also used for procaine allergic patients.
Drawings
FIG. 1 is a graph showing the in vitro drug release of the solutions of example 1, bupivacaine and tricine;
FIG. 2 is a graph showing the in vitro cytotoxicity of example 1 and of the solutions of bupivacaine and tricine;
FIG. 3 is a graph showing the anesthetic effect of example 1, comparative example 2 and 0.9% g/mL physiological saline;
FIG. 4 is an SEM image of a 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer.
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate the invention and together with the embodiments of the invention, serve to explain the invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all embodiments of the invention; all other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the examples of the present invention, unless specifically indicated, the raw materials or treatment techniques are all conventional commercially available raw materials or conventional treatment techniques in the art.
The bupivacaine used in the invention is purchased from Hubei Jusheng technology Co., ltd; tricaine is available from Hubei Xinrun chemical Co., ltd; 1-ethyl-3-methyl bromoimidazole was purchased from Shanghai blue Chemicals, inc.; methyl methacrylate was purchased from aladine; dibenzoyl peroxide was purchased from wanqing chemical technology limited; phospholipid polyethylene glycol was purchased from Guangzhou Chemie biotechnology; polyoxyethylene fatty alcohol ethers were purchased from south-access Dayao chemicals Co.
Example 1
The invention provides a slow-release anesthetic composition
The slow-release anesthetic composition comprises the following components in parts by weight: 30 parts of long-acting anesthetic compound, 4 parts of emulsifier, 8 parts of surfactant, 1.5 parts of polyoxyethylene fatty alcohol ether and the balance of normal saline; the long-acting anesthetic compound comprises the following components in parts by weight: 20 parts of bupivacaine, 15 parts of tricine and 20 parts of lipid complex.
Wherein the lipid complex comprises the following components in parts by weight: 15 parts of 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer and 8 parts of phospholipid polyethylene glycol.
The preparation method of the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer comprises the following steps:
(1) 0.5g of 1-ethyl-3-methyl imidazole bromide is dissolved in 20mL of 0.1mol/L acetic acid solution to prepare a solution A, then 10mL of ethanol is dripped into the solution A, and stirring is carried out for 10 minutes at room temperature to prepare a solution B;
(2) 0.5g of dibenzoyl peroxide and 2g of methyl methacrylate are added to solution B at 60℃for a reaction time of 2 hours;
(3) Washing with acetone for 3 times, filtering and collecting to prepare the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate grafted copolymer.
Wherein the emulsifier is polyoxyethylene castor oil; the surfactant is lecithin; the physiological saline is sodium chloride solution with concentration of 0.8 percent g/mL.
The invention also provides a preparation method of the slow-release anesthetic composition, which comprises the following steps:
(1) Dissolving 15 parts of 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer, 8 parts of phospholipid polyethylene glycol, 4 parts of polyoxyethylene castor oil, and 1.5 parts of lecithin and polyoxyethylene fatty alcohol ether in acetone to prepare an oil phase A;
(2) Stirring 20 parts of bupivacaine, 15 parts of tricine and 0.8% g/mL of physiological saline until the bupivacaine and the physiological saline are completely dissolved, and preparing a water phase B;
(3) Next, the oil phase a is ultrasonically emulsified in the ice-bath water phase B for 5 minutes to prepare a mixture;
(4) And finally, stirring the mixture obtained in the step (3) for 12 hours at room temperature, evaporating acetone, centrifugally collecting to obtain the slow-release anesthetic composition, and washing with ultrapure water.
Example 2
The invention provides a slow-release anesthetic composition
The slow-release anesthetic composition comprises the following components in parts by weight: 10 parts of long-acting anesthetic compound, 1 part of emulsifying agent, 1 part of surfactant, 0.5 part of polyoxyethylene fatty alcohol ether and the balance of normal saline; the long-acting anesthetic compound comprises the following components in parts by weight: 15 parts of bupivacaine, 10 parts of tricine and 15 parts of lipid complex.
Wherein the lipid complex comprises the following components in parts by weight: 10 parts of 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer and 1 part of phospholipid polyethylene glycol.
The preparation method of the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer comprises the following steps:
(1) 0.5g of 1-ethyl-3-methyl imidazole bromide is dissolved in 20mL of 0.1mol/L acetic acid solution to prepare a solution A, then 10mL of ethanol is dripped into the solution A, and stirring is carried out for 10 minutes at room temperature to prepare a solution B;
(2) 0.5g of dibenzoyl peroxide and 1.5g of methyl methacrylate are added to solution B at a temperature of 60℃for a reaction time of 2 hours;
(3) Washing with acetone for 3 times, filtering and collecting to prepare the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate grafted copolymer.
Wherein the emulsifier is sorbitol monostearate; the surfactant is stearic acid; the physiological saline is sodium chloride solution with the concentration of 0.6 percent g/mL.
Furthermore, the present invention provides a method for preparing a sustained-release anesthetic composition, which is performed with reference to example 1.
Example 3
The invention provides a slow-release anesthetic composition
The slow-release anesthetic composition comprises the following components in parts by weight: 50 parts of long-acting anesthetic compound, 6 parts of emulsifying agent, 15 parts of surfactant, 2.5 parts of polyoxyethylene fatty alcohol ether and the balance of normal saline; the long-acting anesthetic compound comprises the following components in parts by weight: 35 parts of bupivacaine, 25 parts of tricine and 25 parts of lipid complex.
Wherein the lipid complex comprises the following components in parts by weight: 20 parts of 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer and 15 parts of phospholipid polyethylene glycol.
The preparation method of the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer comprises the following steps:
(1) 0.5g of 1-ethyl-3-methyl imidazole bromide is dissolved in 20mL of 0.1mol/L acetic acid solution to prepare a solution A, then 10mL of ethanol is dripped into the solution A, and stirring is carried out for 10 minutes at room temperature to prepare a solution B;
(2) 0.5g of dibenzoyl peroxide and 2.5g of methyl methacrylate are added to solution B at a temperature of 60℃for a reaction time of 2 hours;
(3) Washing with acetone for 3 times, filtering and collecting to prepare the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate grafted copolymer.
Wherein the emulsifier is sodium dodecyl sulfate; the surfactant is fatty glyceride; the physiological saline is sodium chloride solution with the concentration of 0.9 percent g/mL.
Furthermore, the present invention provides a method for preparing a sustained-release anesthetic composition, which is performed with reference to example 1.
Comparative example 1
This comparative example provides a slow-release anesthetic composition which differs from example 1 only in that the slow-release anesthetic composition does not contain bupivacaine, and the remaining components and the component contents are the same as in example 1.
Comparative example 2
This comparative example provides a slow-release anesthetic composition which differs from example 1 only in that the slow-release anesthetic composition does not contain tricaine, and the remaining components and the component contents are the same as example 1.
Performance test (1)
According to the pharmaceutical stability guidelines, the stability of example 1, water phase B and the direct mixture of oil phase A and water phase B are mainly examined, and the examination content mainly comprises the pH, content and related substances of the sample.
Examine the variation of example 1 under strong light conditions on days 0, 5, 10; examining the change of the water phase B in the 0 th, 5 th and 10 th days under strong light conditions, and examining whether the water phase B is stable or not because the water phase B contains the bupivacaine and the tricaine; examining the change of the direct mixture of the oil phase A and the water phase B in days 0, 5 and 10 under strong light conditions; directly mixing water phase B, oil phase A and water phase B, slowly releasing anesthetic composition, respectively placing into small beakers, sealing with tinfoil paper, placing into medicine strong illumination box, regulating light intensity to 4500 lx+ -00 lx, standing for 10 days, respectively at day 0, day 5 and day 10, sampling, detecting, and recording data.
TABLE 1 stability test under high humidity conditions
As a result of analysis, as shown in Table 1, the sample of example 1 was left under high humidity conditions, and the contents and the related substances were all in accordance with the standards; placing the water phase B containing the bupivacaine and the tricaine under a high-humidity condition, wherein related substances and contents meet the requirements; placing the direct mixture of the oil phase A and the water phase B under high humidity, wherein the related substances and the content of the substances do not meet the standards on the 5 th day, and the mixture is very unstable; thus, under high humidity conditions, mixing oil phase A and water phase B according to the preparation method and then standing, and detecting are more stable than directly mixing oil phase A and water phase B.
Performance test (2)
Examining the in vitro drug release condition of the slow-release anesthetic composition, analyzing the content of the bupivacaine and the trimercacaine in the slow-release anesthetic composition by adopting a reversed-phase high-performance liquid chromatography (Agilent 1100 series), injecting 10mL of the slow-release anesthetic composition into a mobile phase of 50% PBS (pH=7.4) and 50% acetonitrile (0.1% TFA) at a flow rate of 1mL/min, and passing through a reversed-phase chromatographic column (Zorbax EclipseSDB-C18) with an elution wavelength of 260 nm.
The release of the slow-release anesthetic composition was studied using a dialysis bag method, which retains the lipid complex but allows the free drug to diffuse into the dissolution medium; the dialysis bags were filled with the solution of example 1 and with the solution of bupivacaine and tricivacaine (2 mL) respectively, and then the bags were placed in glass beakers containing 0.2L of PBS (ph=7.4), stirred at 37.0 ℃ ± 0.5 ℃ at a speed of 100rpm, 1mL of medium was taken at preset time intervals (0,0.5,1,2,3,6,9, 12, 24, 48, 72, 96 hours), the content of bupivacaine and tricivacaine was determined by HPLC, and equal amounts of PBS (1 mL) maintained at the same temperature were added at each time point to ensure the sink conditions; example 1 and in vitro drug release behavior of the bupivacaine and trimethocaine solutions are expressed as cumulative bupivacaine and trimethocaine release (%)/time.
As a result, as shown in fig. 1, the release rates of the bupivacaine and the trimercacaine from the solutions were high, and the release amounts of the drugs were 80% or more in 0.5 hours, and the sustained release behaviors of the bupivacaine and the trimercacaine carried by the lipid complex in example 1 were exhibited, and only 50% of the drugs were released after 24 hours. The time point at which example 1 reached 80% or more of the drug release was 72 hours.
Performance test (3)
Example 1 cytotoxicity of the solution of Butanocaine and Tricaine BALB/c-3T3 cells were tested by MTT assay. Seeding in 48 well plates at a seeding density of 104 cells per well, followed by culturing FBS and 5% co in DMEM supplemented with 10% 2 The following antibiotics were left at 37 ℃ for 24 hours; the in vitro cytotoxicity of example 1 and the bupivacaine and trimecaine solutions was assessed by measuring BALB/c-3T3 fibroblast viability.
Results analysis, as shown in fig. 2, example 1 has moderate effect on cell viability at all concentrations from 1 to 100, no significant change was found; in high concentrations of bupivacaine and trimecaine solutions, cell viability decreased.
Performance test (4)
The anesthetic effect of the slow-release anesthetic composition in rats was evaluated by a radiant heat tail flick latency test, and samples of physiological saline of example 1, comparative example 2 and 0.9% were sequentially smeared on the tails of rats and placed in a plastic box with 5-6 cm ventral surface of the distal end of the tail placed on a 0.5 cm hole under which an infrared radiation bulb was placed. To avoid tissue damage, a cut-off time of 10 seconds is set; the Maximum Possible Effect (MPE) was calculated according to the formula and the baseline latency was calculated as the average of three different measurements taken every 10 minutes.
MPE (%) = (test latency-baseline latency)/(deadline-baseline latency) ×100.
As shown in FIG. 3, compared with the physiological saline control group with 0.9% g/mL, the anesthesia time of the comparative example 1 and the comparative example 2 is short, the effect is quick, and the peak is reached within 1 hour; the anesthetic effect of example 1 lasted 10 hours, indicating that the slow-release anesthetic composition was effective in extending the duration of local anesthesia.
It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
The invention and its embodiments have been described above with no limitation, and the actual construction is not limited to the embodiments of the invention as shown in the drawings. In summary, if one of ordinary skill in the art is informed by this disclosure, a structural manner and an embodiment similar to the technical solution should not be creatively devised without departing from the gist of the present invention.
Claims (10)
1. The slow-release anesthetic composition is characterized by comprising the following components in parts by weight: 10-50 parts of long-acting anesthesia compound, 1-6 parts of emulsifier, 1-15 parts of surfactant, 0.5-2.5 parts of polyoxyethylene fatty alcohol ether and the balance of physiological saline; the long-acting anesthetic compound comprises the following components in parts by weight: 10-50 parts of bupivacaine, 5-35 parts of tricine and 10-30 parts of lipid complex.
2. The slow release anesthetic composition according to claim 1, wherein the long-acting anesthetic complex comprises the following components in parts by weight: 15-35 parts of bupivacaine, 10-25 parts of tricine and 15-25 parts of lipid complex.
3. The slow-release anesthetic composition according to claim 2, wherein: the lipid complex comprises the following components in parts by weight: 10-20 parts of 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer and 1-15 parts of phospholipid polyethylene glycol.
4. The slow release anesthetic composition according to claim 3, wherein the preparation method of the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer comprises the steps of:
(1) 1-ethyl-3-methyl imidazole bromide is dissolved in 0.1mol/L acetic acid solution to prepare solution A, then 10mL of ethanol is dripped into the solution A, and stirring is carried out for 10 minutes at room temperature to prepare solution B;
(2) Dibenzoyl peroxide and methyl methacrylate are added into the solution B, the temperature is 60 ℃, and the reaction time is 2 hours;
(3) Washing with acetone for 3 times, filtering and collecting to prepare the 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate grafted copolymer.
5. The slow-release anesthetic composition according to claim 4, wherein: the mass ratio of the 1-ethyl-3-methyl brominated imidazole to the methyl methacrylate is 1:3-1:5.
6. The slow-release anesthetic composition according to claim 5, wherein: the emulsifier comprises one or more of sorbitol monostearate, polyoxyethylated castor oil, and sodium lauryl sulfate.
7. The slow-release anesthetic composition according to claim 6, wherein: the surfactant comprises one or more of sodium cholate, stearic acid, lecithin and fatty acid glyceride.
8. The slow-release anesthetic composition according to claim 7, wherein: the physiological saline is sodium chloride solution with the concentration of 0.6-0.9% g/mL.
9. A method of preparing a slow release anesthetic composition as claimed in claim 8, wherein: the method specifically comprises the following steps:
(1) Dissolving 10-20 parts of 1-ethyl-3-methyl brominated imidazole-polymethyl methacrylate graft copolymer, 1-15 parts of phospholipid polyethylene glycol, 1-6 parts of emulsifier, 1-15 parts of surfactant and 0.5-2.5 parts of polyoxyethylene fatty alcohol ether in acetone to prepare an oil phase A;
(2) Stirring 15-35 parts of bupivacaine, 10-25 parts of tricine and 0.6-0.9% g/mL of physiological saline until the bupivacaine and the physiological saline are completely dissolved, and preparing a water phase B;
(3) Next, the oil phase a is ultrasonically emulsified in the ice-bath water phase B for 5 minutes to prepare a mixture;
(4) And finally, stirring the mixture obtained in the step (3) for 12 hours at room temperature, evaporating acetone, centrifugally collecting to obtain the slow-release anesthetic composition, and washing with ultrapure water.
10. The method of preparing a slow release anesthetic composition as claimed in claim 9, wherein: the pH value of the slow-release anesthetic composition is less than or equal to 8.0.
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| CN202310227641.XA CN116139137B (en) | 2023-03-10 | 2023-03-10 | Sustained-release anesthetic composition and preparation method thereof |
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| CN116139137B CN116139137B (en) | 2023-09-29 |
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| CN117752644A (en) * | 2023-12-29 | 2024-03-26 | 海南三帝制药有限公司 | Anesthetic containing tricaine, and preparation method and application thereof |
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| CN117752644B (en) * | 2023-12-29 | 2024-06-18 | 海南三帝制药有限公司 | Anesthetic containing tricaine, and preparation method and application thereof |
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