CN114073675A - A kind of propofol mixed micelle and preparation method thereof - Google Patents
A kind of propofol mixed micelle and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a propofol mixed micelle and a preparation method thereof, wherein the propofol mixed micelle comprises propofol, polyethylene glycol derivatives and other pharmaceutically acceptable auxiliary materials, and the polyethylene glycol derivatives are one or two of polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) or polyethylene glycol-15 hydroxystearate (Solutol HS 15). The invention adopts a film dispersion method, the propofol and the polyethylene glycol derivative are dissolved by an organic phase, the organic solvent is removed by rotary evaporation, and the drug-carrying micelle is obtained by film passing after the water phase is hydrated.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a propofol mixed micelle and a preparation method thereof.
Background
Propofol (Propofol, Prop) is a commonly used clinical intravenous anesthetic, has the characteristics of quick response and short action time, and is commonly used for inducing and maintaining anesthesia. Propofol is highly hydrophobic, and the initially marketed preparation is an injection solubilized with polyoxyethylene castor oil (Cremophor EL) micelles, but is rapidly withdrawn from the market due to allergic reactions caused by the polyoxyethylene castor oil and injection pain of the preparation. At present, the O/W type fat emulsion injection is used, the clinical application concentration is 10mg/ml, soybean oil is used as an oil phase, phospholipid is used as an emulsifier, and glycerol is used as an osmotic pressure regulator, so that the problem that propofol is difficult to dissolve in water is solved, and the pain incidence rate is reduced. However, domestic clinical studies show that the incidence of pain caused by injection of the fat emulsion injection is still as high as 40%. Because the fat emulsion is a thermodynamically unstable system and is not heat-resistant and frozen, the requirement on the storage temperature is high. Therefore, a novel injection preparation which can improve the solubility and stability of propofol and reduce injection pain is urgently needed to meet clinical requirements.
CN200710188561.9 discloses a compound propofol injection containing analgesic and a preparation method thereof, and although the injection has the dual effects of anesthesia and analgesia, the prescription introduces additional analgesic drugs, thereby further increasing the adverse reaction and medication risk of patients.
CN200710017685.0 discloses a long-circulating fat emulsion propofol preparation, propofol, vegetable oil, lecithin, polyethylene glycol phospholipid, oleic acid, vitamin E and the like are prepared into fat emulsion, the obtained preparation can inhibit the removal of in-vivo medicines and improve the curative effect of the medicines, but the components are complex, the preparation process is complicated, and the propofol stability is reduced due to the heating in the preparation method.
CN200710169846.8 discloses a micro-emulsion composition of propofol, which contains propofol, Solutol HS 15, oil for injection, phospholipid and other water-soluble components. Although the hemolytic effect of propofol is improved to a certain extent, the preparation process is complex and tedious, and heating is required, so that the structure of propofol which is sensitive to temperature is changed, the content of impurities is increased, and the risk of medication is increased.
CN201110320553.1 discloses a propofol medium-long chain fat emulsion, which comprises propofol, soybean oil, medium-chain triglyceride, glycerol, lecithin, sodium bicarbonate, oleic acid and water for injection. The process is prepared by heating, and can cause the structure of propofol to be changed and the stability to be reduced.
In the prior art, the free drug concentration of the prepared propofol fat emulsion is too high, the preparation process is complex and heating is needed, so that the stability of propofol is reduced, the compliance of patients is reduced, and the medication risk is increased.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a propofol mixed micelle which is simple in components, safe and effective, and a preparation method thereof. According to the invention, the amphiphilic polymer polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) and polyethylene glycol-15 hydroxystearate (Solutol HS 15) are combined for use, so that an excellent propofol micelle preparation is prepared, the solubility of propofol is effectively improved, few free drugs are used, the entrapment rate is high, the pain of patients is effectively relieved, the compliance is improved, the preparation process is simple, and the production is easy.
The invention provides a propofol mixed micelle, which comprises propofol and polyethylene glycol derivatives, wherein the polyethylene glycol derivatives are one or two of polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) or polyethylene glycol-15 hydroxystearate (Solutol HS 15),
the concentration of each component is as follows:
propofol 0.1-10mg/ml
PEG-DSPE 2-50mg/ml
Solutol HS 15 0-250mg/ml。
In the invention, the polyethylene glycol derivative is the combination of PEG-DSPE and Solutol HS 15.
In the invention, the PEG-DSPE is PEG with the PEG molecular weight of 20002000-DSPE。
In the invention, the concentration of each component is as follows:
propofol 0.1-10mg/ml
PEG-DSPE 2-20mg/ml
Solutol HS 15 0.5-100mg/ml。
In the invention, the propofol mixed micelle is isotonic with blood plasma.
In the invention, pharmaceutically acceptable auxiliary materials are added into the propofol mixed micelle.
In the invention, the pharmaceutically acceptable other auxiliary materials are osmotic pressure regulators.
In the present invention, the osmotic pressure regulator is physiological saline.
The invention provides a preparation method of a propofol mixed micelle, which comprises the following specific steps: weighing propofol and polyethylene glycol derivatives, adding an organic solvent for dissolving and mixing, carrying out rotary evaporation on the organic solvent to form a layer of film, adding an aqueous phase for vortex, carrying out magnetic stirring, and then filtering the film to obtain the propofol mixed micelle.
Preferably, the propofol, the polyethylene glycol derivative PEG-DSPE and/or the Solutol HS 15 are weighed firstly, the organic solvent methanol is added for dissolving and mixing, the organic solvent methanol is evaporated in a rotating mode to form a layer of film, the physiological saline is added for vortex, the film passes through a 0.45-micrometer filter membrane after magnetic stirring, and the propofol mixed micelle is obtained.
Preferably, at the temperature of 40 ℃, the Solutol HS 15 is melted, the propofol, the polyethylene glycol-distearoyl phosphatidyl ethanolamine and the melted Solutol HS 15 are weighed, an organic solvent methanol is added for dissolving and mixing, the organic solvent methanol is evaporated in a rotating way to form a layer of film, physiological saline is added for vortex for 3-5min, the mixture is stirred by magnetic force for 0.5-1h and then is filtered by a 0.45 mu m filter membrane, and the propofol micelle is obtained.
Compared with the prior art, the invention has the following beneficial effects:
(1) the solubility of propofol is effectively improved; (2) the free drug concentration of propofol is reduced, and the patient compliance is improved;
(3) the hemolysis percentage of propofol is reduced, and the medication safety is improved; (4) the preparation process is simple, heating is not needed, and the stability of the propofol is improved.
Drawings
FIG. 1 is a graph of the particle size distribution of propofol micelles from example 1.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are given solely for the purpose of illustration and not as limitations of the present invention, and therefore, simple modifications of the present invention in the context of the methods of the present invention are intended to fall within the scope of the claims.
Example 1
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000DSPE and Solutol HS 15, adding methanol for dissolving and mixing, performing rotary evaporation on the methanol to form a layer of film by adopting a film dispersion method, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 2
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000DSPE and Solutol HS 15, adding methanol for dissolving and mixing, performing rotary evaporation on the methanol to form a layer of film by adopting a film dispersion method, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 3
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000-DSPE, Solutol HS 15, adding methanol to dissolve and mix, adopting film dispersion method, rotary evaporating methanol to form a layerAnd (3) adding 5ml of physiological saline into the film, vortexing for 5min, magnetically stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 4
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000DSPE and Solutol HS 15, adding methanol for dissolving and mixing, performing rotary evaporation on the methanol to form a layer of film by adopting a film dispersion method, adding 5ml of physiological saline, performing vortex for 3min, performing magnetic stirring for 0.5h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 5
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000DSPE and Solutol HS 15, adding methanol for dissolving and mixing, performing rotary evaporation on the methanol to form a layer of film by adopting a film dispersion method, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 6
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000-DSPE, Solutol HS 15, adding chloroform for dissolving and mixing, performing thin film dispersion method, performing rotary evaporation on methanol to form a thin film, adding 5ml of normal saline, and performing vortexAnd (5) magnetically stirring for 1h, and filtering with a 0.45-micron filter membrane to obtain the mixed micelle.
Example 7
1) Propofol mixed micelle formulation:
concentration of the components
Propofol 1mg/ml
PEG2000-DSPE 20mg/ml
2) The preparation process comprises the following steps:
weighing prescription dose of propofol and PEG2000And (3) adding chloroform into the DSPE to dissolve and mix, performing rotary evaporation on methanol by adopting a film dispersion method to form a layer of film, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Example 8
1) Propofol mixed micelle formulation:
2) the preparation process comprises the following steps:
dissolving Solutol HS 15 at 40 deg.C, and weighing propofol and PEG in prescribed amount2000-DSPE and Solutol HS 15, adding chloroform for dissolving and mixing, performing rotary evaporation on methanol by adopting a film dispersion method to form a layer of film, adding 5ml of physiological saline, performing vortex for 5min, performing magnetic stirring for 1h, and then filtering through a 0.45-micrometer filter membrane to obtain the mixed micelle.
Comparative example 1:
1) prescription:
2) the preparation process comprises the following steps:
heating soybean oil, lecithin, sodium oleate and PEG2000-DSPE of the prescription amount to 75 ℃ under the protection of nitrogen, stirring for 10min to fully dissolve the added auxiliary materials, adding propofol and vitamin E of the prescription amount, dissolving uniformly, taking 800ml of water for injection, adding glycerol, adding oil solution containing the medicine into glycerol aqueous solution under the condition of shearing and stirring under the protection of nitrogen to prepare colostrum, adjusting the total amount to 1000ml, homogenizing for 5-8 times under high pressure, adjusting the pH value to 7.0-8.0 and filtering.
Comparative example 2:
1) prescription
2) The preparation process comprises the following steps:
dissolving lecithin in MCT (methyl cellulose acetate) at 65 ℃ in a water bath, adding Solutol HS 15 and propofol, and uniformly stirring to obtain an oil phase; dispersing glycocholic acid, calcium ethylene diamine tetracetate and glycerol in about 60ml of water, and adjusting the pH to 7 by using a sodium hydroxide solution to change the glycocholic acid into sodium glycocholate to obtain a water phase; adding the water phase into the oil phase under stirring at about 60 deg.C, stirring to obtain microemulsion, filtering, and adding water to 100 ml.
Verification example 1:
1. particle size analysis
The formulation solutions obtained in examples 1 to 8 and comparative examples 1 to 2 were measured for dynamic light scattering particle diameter, polydispersity index (PDI) by a particle size analyzer.
TABLE 1 particle size and polydispersity index for examples and comparative examples
| Examples | Particle size (nm) | Polydispersity index (PDI) |
| Example 1 | 29.9 | 0.166 |
| Example 2 | 33.42 | 0.201 |
| Example 3 | 21.08 | 0.193 |
| Example 4 | 13.55 | 0.110 |
| Example 5 | 15.96 | 0.151 |
| Example 6 | 12.57 | 0.199 |
| Example 7 | 28.13 | 0.199 |
| Example 8 | 25.24 | 0.242 |
| Comparative example 1 | 189.65 | 0.389 |
| Comparative example 2 | 11.52 | 0.358 |
The mixed micelle prepared by the method has smaller particle size, PDI (polymer induced degradation) less than 0.3, is uniformly dispersed, and is obviously superior to the prior art.
2. Free drug detection
The propofol mixed micelles obtained in examples 1-8 were collected and 400. mu.L of the propofol mixed micelles were loaded into an ultrafiltration centrifuge tube (3K, Millipore), ultracentrifuged at 3000rpm for 20min, and the lower aqueous phase was analyzed by HPLC using a chromatographic column, Eclipse Plus C185. mu.m, 4.6X250 mm; the mobile phase is phosphoric acid water solution (A) with pH 2 and acetonitrile (B); the detection wavelength is 270 nm; the sample volume is 20 mu L; the flow rate is 1 ml/min; gradient elution.
TABLE 2 gradient elution method
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 50 | 50 |
| 6 | 30 | 70 |
| 13 | 30 | 70 |
| 14 | 50 | 50 |
| 16 | 50 | 50 |
TABLE 3 results of measurement of free concentration in examples 1 to 8 and comparative examples 1 to 2
The micelle free drug concentration obtained by the invention is lower, compared with the prior art, the micelle free drug concentration is reduced by at least 68.1%, the pain degree of a patient during injection can be obviously reduced, and the compliance of the patient is effectively improved.
3. Encapsulation efficiency test
The propofol mixed micelle obtained in the embodiments 1 to 8 adopts the liquid phase method to detect the propofol concentration, 100 mu L of the obtained micelle solution is taken, 900 mu L of acetonitrile is added for demulsification, the propofol concentration is detected by HPLC, and the encapsulating rate of the propofol is calculated according to the following formula.
Wherein: cGeneral assemblyAs the total propofol concentration in the micelle, CFree formIs the free concentration of propofol in the micelles.
TABLE 4 results of encapsulation efficiency measurements of examples 1-8
| Examples | Encapsulation efficiency (%) |
| Example 1 | 76.9 |
| Example 2 | 69.9 |
| Example 3 | 53.9 |
| Example 4 | 70.3 |
| Example 5 | 87.6 |
| Example 6 | 82.6 |
| Example 7 | 60.9 |
| Example 8 | 67.36 |
4. Hemolysis test
5ml of blood is taken from an SD rat, the SD rat is centrifuged at 3000rpm for 10min to remove blood plasma, red blood cells are left to be precipitated, 10 times of physiological saline is added, the centrifugation step is repeated for three times, the supernatant is clear and colorless, and the red blood cell precipitate is prepared into 2 percent suspension by the physiological saline for standby. Adding 800 μ l of the preparations obtained in examples 1-8 into an EP tube, adding 200 μ l of erythrocyte suspension, shaking uniformly, placing in 37 ℃ and slowly shaking for 2h, centrifuging the incubated tube solution at 3000rpm for 10min, taking the supernatant, transferring the supernatant into a 96-well plate, reading the OD value of each tube solution by a microplate reader, wherein the selected wavelength is 545nm, the positive control is distilled water, and the negative control is physiological saline. Percent hemolysis was calculated using the following equation.
Hemolysis ratio (%) - (ODt-ODnc)/(ODpc-ODnc) x 100%
ODt- -absorbance in test tubes;
ODnc — absorbance of negative tubes;
ODpc-positive absorbance.
TABLE 5 hemolysis results of examples 1 to 8
| Examples | Percent hemolysis (%) |
| Example 1 | 4.37 |
| Example 2 | 3.15 |
| Example 3 | 3.84 |
| Example 4 | 5.19 |
| Example 5 | 2.61 |
| Example 6 | 9.34 |
| Example 7 | 7.51 |
| Example 8 | 12.9 |
The hemolysis percentage of the embodiments 1 to 8 of the invention is less than 15 percent, which is obviously superior to the prior art and effectively improves the safety.
Claims (10)
1. A propofol mixed micelle, which is characterized in that: the composition of the compound comprises propofol and polyethylene glycol derivatives, wherein the polyethylene glycol derivatives are one or two of polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) or polyethylene glycol-15 hydroxystearate (Solutol HS 15),
the concentration of each component is as follows:
propofol 0.1-10mg/ml
PEG-DSPE 2-50mg/ml
Solutol HS 15 0-250mg/ml。
2. Propofol mixed micelle according to claim 1, wherein: the polyethylene glycol derivative is the combination of PEG-DSPE and SolutolHS 15.
3. Propofol mixed micelle according to claim 1, wherein: the PEG-DSPE is PEG with PEG molecular weight of 20002000-DSPE。
4. Propofol mixed micelle according to claim 1, wherein: the concentration of each component is as follows:
propofol 0.1-10mg/ml
PEG-DSPE 2-20mg/ml
Solutol HS 15 0.5-100mg/ml。
5. Propofol mixed micelle according to claim 1, wherein: the propofol mixed micelles are isotonic with plasma.
6. Propofol mixed micelle according to claim 1, wherein: the propofol mixed micelle is added with pharmaceutically acceptable auxiliary materials.
7. Propofol mixed micelle according to claim 6, characterized in that: the pharmaceutically acceptable other auxiliary materials are osmotic pressure regulators.
8. Propofol mixed micelle according to claim 7, wherein: the osmotic pressure regulator is normal saline.
9. A process for the preparation of propofol mixed micelles as claimed in claim 1, wherein: the method comprises the following specific steps: weighing propofol and polyethylene glycol derivatives, adding an organic solvent for dissolving and mixing, carrying out rotary evaporation on the organic solvent to form a layer of film, adding an aqueous phase for vortex, carrying out magnetic stirring, and then filtering the film to obtain the propofol mixed micelle.
10. The method for preparing propofol mixed micelles of claim 9, wherein: weighing propofol, polyethylene glycol derivative PEG-DSPE and/or Solutol HS 15, adding an organic solvent methanol for dissolving and mixing, carrying out rotary evaporation on the organic solvent methanol to form a layer of film, adding physiological saline for vortex, carrying out magnetic stirring, and then, filtering through a 0.45-micrometer filter membrane to obtain the propofol mixed micelle.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024108501A1 (en) * | 2022-11-24 | 2024-05-30 | 中国科学院深圳先进技术研究院 | Pharmaceutical use of propofol in anti-anxiety drug, and anti-anxiety pharmaceutical preparation |
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Cited By (1)
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| WO2024108501A1 (en) * | 2022-11-24 | 2024-05-30 | 中国科学院深圳先进技术研究院 | Pharmaceutical use of propofol in anti-anxiety drug, and anti-anxiety pharmaceutical preparation |
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