CN101411685B - Intravenous anesthetics 2,6-diisopropyl phenol microemulsion composition and method of making the same - Google Patents
Intravenous anesthetics 2,6-diisopropyl phenol microemulsion composition and method of making the same Download PDFInfo
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Abstract
The invention provides intravenous anesthetics 2, 6-diisopropyl phenol microemulsion composition, which is characterized by containing 2, 6-diisopropyl phenol, Solutol HS15, oil for injection, phospholipids or other aqueous components. The invention discloses a preparation method for the microemulsion composition at the same time. The grain diameter of the microemulsion composition is less than 100 nanometers, and the microemulsion composition is transparent in appearance, has slight opalescence, does not cause the occurrence of hemolysis, and can be used for intravenous injection and administration.
Description
Technical field
The present invention relates to a kind of intravenous anesthetic 2,6-diisopropyl phenol microemulsion composition and preparation method thereof.
Background technology
2, (common name: propofol propofol) is a kind of maincenter anesthetics, by activating GABA receptor-chloride ion complex, the performance sedative-hypnotic effect to the 6-diisopropyl phenol.2, the 6-diisopropyl phenol is applicable to all size operation at all ages and classes and position clinically, and characteristics such as, revive rapid, few side effects rapid-action because of having are subjected to clinical popular welcome.
2, the 6-diisopropyl phenol, 19 ℃ of fusing points, pKa are 11.2, the 6-diisopropyl phenol is fat-soluble strong, and its LogP value is 3.842, and the dissolubility under the room temperature in water is about 124mg/L.Because 2, therefore 6-diisopropyl phenol poorly water-soluble often needs to use the technology of fat milk or microemulsion to prepare.
2,6-diisopropyl phenol injection causes injection pain easily, bibliographical information 2 is arranged, the injection pain that 6-diisopropyl phenol injection causes is directly to be contacted with the nervus vasculairs tip by the free drug in the aqueous solution, excite plasma kallikrein-kinin system to cause, and the generation of injection pain and aqueous phase free 2,6-diisopropyl phenol concentration is relevant, aqueous phase free 2,6-diisopropyl phenol concentration is high more, easy more injection pain (document 1:Yamakage M, the Iwasaki S of causing, Satoh J, et al.Changes in concentrations of free propofol by modification of the solution.
Anesth Analg.2005,101 (2): 385-388; Document 2:M ü ller RH, Harnisch S.Physicochemical characterization of propofol-loaded emulsions andinteraction with plasma proteins.Eur Hosp Pharm, 2000,6:24-31), therefore dissociate 2,6-diisopropyl phenol concentration is the important indicator of its preparation research, use suitable technology to reduce aqueous phase free 2,6-diisopropyl phenol concentration is to reduce by 2, one of key of 6-diisopropyl phenol injection injection pain.Find also that by research propofol has stronger hemolytic, destroys erythrocyte easily, causes hemolytic generation, if dissociate 2 in the water in the injection, 6-diisopropyl phenol concentration height, then aqueous phase free 2, the 6-diisopropyl phenol can directly contact with erythrocyte, destroys erythrocyte, produces haemolysis.Because hemolytic research is the requisite safety research of injection medicine, can not produce during the external hemolytic experiment of injection medicine haemolysis (document 3: " technological guidance's principle of chemicals zest and hemolytic research " [S]. Beijing: State Food and Drug Administration's medicine is evaluated the center), therefore prescription and the technology selecting to be fit to prepare 2, and 6-diisopropyl phenol injection is extremely important.
Patent 00809224.9 uses the micro emulsion composition technology to prepare 2,6-diisopropyl phenol injection, contain 2 in the said composition, 6-diisopropyl phenol 1-2%, pool Luo Samu 0.1-10%, further contain the cosurfactant of at least a Solutol of being selected from HS 15, lecithin, Labrasol, polyoxy ten oleyl ethers, tween, ethanol and Polyethylene Glycol, the amount of wherein said Solutol HS 15 is 0.1-10%, and the amount of lecithin is 0.1-5%.Though said composition has thermodynamically stable advantage, can go out microorganism by aseptic filtration, be easy to preparation, can reduce side effect such as thromboembolism and haemolysis, but we find after deliberation, compositions aqueous phase free 2 according to embodiment 1 preparation, 6-diisopropyl phenol concentration is higher, and still has stronger hemolytic and (see experimental example 3 for details, 4), its reason is that said composition is difficult to 2, the 6-diisopropyl phenol is wrapped in hydrophobic phase, thereby cause aqueous phase to dissociate 2,6-diisopropyl phenol concentration height, and cause it to have stronger hemolytic, this technology is unfavorable for reducing pain on injection, is unfavorable for improving patient's compliance.
Summary of the invention
Contain 2 at prior art, the micro emulsion composition of 6-diisopropyl phenol easily causes injection pain and the shortcoming that still has stronger hemolytic, the invention provides a kind of intravenous anesthetic 2,6-diisopropyl phenol microemulsion composition and preparation method thereof, said composition can be well with 2, and the 6-diisopropyl phenol is wrapped in its thin aqueous phase, aqueous phase free 2,6-diisopropyl phenol concentration is low, to preparation do not produce haemolysis, help realizing painlessization administration; Said composition is a kind of transparent, thermodynamically stable preparation simultaneously, and preparation is simple, and condition of storage requires low.
Technical scheme of the present invention is as follows:
A kind of intravenous anesthetic 2 is provided, and the 6-diisopropyl phenol microemulsion composition is characterized in that, described compositions contains:
A) 2, the 6-diisopropyl phenol;
b)Solutol?HS?15；
C) oil for injection;
D) phospholipid; With
E) other water compositions.
This micro emulsion composition injection for intravenous is used.
In this micro emulsion composition, Solutol HS 15 uses as emulsifying agent, and phospholipid uses as co-emulsifier.
Described compositions can also contain another kind of co-emulsifier cholate (or its acid group).
Described 2, the amount of 6-diisopropyl phenol can be 1-2% (weight), preferred 1% (weight).
The amount of described Solutol HS 15 can be 1-12% (weight), preferred 3-8% (weight).
Described oil for injection can be selected from those to 2, the oil for injection that 6-diisopropyl phenol affinity is higher, for example synthetic or natural fatty acid, fatty acid triglycercide, or other injectable oil or their mixture.Wherein fatty acid triglycercide can be selected from medium chain triglyceride, soybean oil or other injectable with oil or their mixture, is preferably medium chain triglyceride.
The amount of described oil for injection can be 1-7% (weight), preferred 3-6% (weight).
Described phospholipid can be selected from Ovum Gallus domesticus Flavus lecithin, soybean lecithin or other injection phospholipid or their mixture, and its amount is 0.1-5% (weight), preferred 1-3% (weight).
Described cholate can be selected from pharmaceutically acceptable salt class a kind of of glycocholic acid, deoxycholic acid or other injection cholic acid or its mixture, and its amount is 0.1-1.5% (weight) (in acid group), preferred 0.2-1% (weight) (in acid group).
The particle diameter of described micro emulsion composition is usually less than 100nm, appearance transparent, little band opalescence and be thermodynamically stable.Compositions of the present invention can be used for intravenous injection.
Described other water compositions are selected from any one or a few in the acceptable isoosmotic adjusting agent of pharmacy, pH regulator agent, metal ion chelation agent, the antioxidant.
Preferably, described compositions is that blood plasma is isoosmotic.
Described isoosmotic adjusting agent can be selected from one or more in glucose, glycerol, sodium chloride or other injectable usefulness isoosmotic adjusting agent.
Preferably, the pH of described compositions is 5-8.
Described pH regulator agent can be selected from one or more in sodium hydroxide, hydrochloric acid or usefulness pH regulator agent of other injectable or its esters, is preferably sodium hydroxide or hydrochloric acid.
Described metal ion chelation agent can be selected from one or more in ethylenediaminetetraacetic acid and its esters.
Described antioxidant can be selected from one or more in vitamin E, vitamin C, sodium sulfite, sodium thiosulfate, L-cysteine or other amino acids antioxidant.
The present invention also provides the method for the above-mentioned described micro emulsion composition of preparation, and this method comprises:
(1) prepare hydrophobic phase: with 2,6-diisopropyl phenol, Solutol HS 15, phospholipid are dissolved in the oil for injection;
(2) preparation water: optional cholate or its acid group are dissolved in the water with other water compositions, and the adjusting pH value is 5-9;
(3) under agitation, water is slowly added thin aqueous phase, continue to stir, obtain micro emulsion composition; Or by the homogenizer homogenizing, make to reach balance rapidly, obtain micro emulsion composition;
(4) with the suitable method degerming of micro emulsion composition process, promptly.
Since 2, the easy oxidation of 6-diisopropyl phenol, and therefore above-mentioned preparation process also can be carried out under nitrogen or other inert gas shieldings.
Used emulsifying agent Solutol HS 15 among the present invention by BASF AG's research and development, meets the standard of modern efficient solubilizing agents, can use the high temperature pressure sterilizing, and its solution viscosity is low, is suitable for drug administration by injection.Solutol HS 15 is by the injectable drug application verification at present.These product are incorporated in the Deutscher Arzneibucs recently, and will be very fast by the officinal authorization of US and European.Employed co-emulsifier phospholipid, cholate are used for the human vein to inject toxicity low among the present invention, and reasonable price, energy mass production, share with Solutol HS 15 and can obtain the good emulsifying effect, obtain the little and stable microemulsion of particle diameter, and the surfactant film of the microemulsion that forms uses Solutol HS 15 more stable more separately, help 2, the 6-diisopropyl phenol is wrapped in hydrophobic region, is not easy to be bled into aqueous phase.Use among the present invention to 2, the higher oil of 6-diisopropyl phenol affinity is that injectable is with oily, can be well with 2, the dissolving of 6-diisopropyl phenol, make 2, the more difficult aqueous phase that is bled into of 6-diisopropyl phenol, most preferred oil for injection is to 2, the medium chain triglyceride that 6-diisopropyl phenol affinity is high (MCT).The amount of the oil for injection that uses among the present invention (1-7%, preferred 3-6%) is significantly less than the consumption (10%) of soybean oil in the listing fat milk, and since MCT in vivo accretion rate therefore be difficult for accumulating in vivo obviously faster than soybean oil, be difficult for causing hyperlipemia.
The formed microemulsion particle diameter of this preparation method is less than 100nm, appearance transparent, pH value is 5-8, but room temperature preserve, can not cause haemolysis, can supply drug administration by injection, what be used to anaesthetize inducing and keeping.
Of the present inventionly contain 2, but the advantage of the anesthetics micro emulsion composition that the injection for intravenous of 6-diisopropyl phenol is used is:
1, use injectable to prepare with adjuvant, safe;
2, prepared micro emulsion composition is transparent, little opalescent solution of being with, and particle diameter is less than 100nm, and said composition is a thermodynamic stable system, storage temperature is required low, but room temperature preserve, but the high temperature pressure sterilizing; Said composition can be carried out the inspection of the insoluble foreign body of injection, to guarantee the safe handling of injection; The said composition particle diameter is little, can not cause thromboembolism;
3, owing to advanced prescription, this micro emulsion composition can be with 2, and the 6-diisopropyl phenol well is wrapped in its hydrophobic region, reduce aqueous phase and dissociate 2, and the amount of 6-diisopropyl phenol helps realizing 2, the painlessization administration of 6-diisopropyl phenol;
4, this micro emulsion composition can not cause hemolytic generation.
The specific embodiment
Provide several 2 by aforementioned summary of the invention in the following example, 6-diisopropyl phenol microemulsion composition, its preparation method and some experimental study contents, but the composition and method of making the same that list in the place that should be appreciated that the present invention is not limited to this, should also be appreciated that term as used herein only is used to describe certain embodiments, and be not limitation of the invention.
Embodiment 1:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 lecithin glycocholic acid MCT sodium ethylene diamine tetracetate calcium glycerol waters for injection add to | 1 5 2.5 0.5 5 0.005 2 100ml |
Preparation method: 65 ℃ of water-baths lecithin is dissolved among the MCT, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; Glycocholic acid, sodium ethylene diamine tetracetate calcium and glycerol are scattered in about 60ml water, transfer pH to 7, make glycocholic acid become NaGC, obtain water with sodium hydroxide solution; About 60 ℃, water is under agitation added in the oil phase, continue to stir, obtain microemulsion, filter, add water to 100ml, embedding, omnidistance nitrogen current protection, sterilization is promptly.
Embodiment 2:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 lecithin NaGC MCT glycerol waters for injection add to | 2 12 5 1.5 (in glycocholic acid), 72 100ml |
Preparation method: 60 ℃ of water-baths lecithin is dissolved among the MCT, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; NaGC and glycerol are scattered in about 60ml water, transfer pH to 5, obtain water; About 60 ℃, water is under agitation added in the oil phase,, make to reach balance rapidly, obtain microemulsion, filter, add water to 100ml by 2 circulations of homogenizer 300Bar homogenizing, embedding, omnidistance nitrogen current protection, sterilization is promptly.
Embodiment 3:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 soybean phospholipid glycocholic acid MCT disodiumedetate glucose injection waters add to | 1 8 2 0.2 1 0.005 4 100ml |
Preparation method: 70 ℃ of water-baths soybean phospholipid is dissolved in the soybean oil, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; Glycocholic acid, disodiumedetate and glucose are scattered in about 60ml water, transfer pH to 6, make glycocholic acid become NaGC, obtain water with sodium hydroxide solution; About 70 ℃, water is under agitation added in the oil phase, continue to stir, obtain microemulsion, filter, add water to 100ml, embedding, sterilization is promptly.
Embodiment 4:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 lecithin glycocholic acid MCT soybean oil disodiumedetate glycerol waters for injection add to | 1 10 3 1 1.5 1.5 0.005 2 100ml |
Preparation method: 60 ℃ of water-baths lecithin is dissolved among the MCT, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; Glycocholic acid, sodium ethylene diamine tetracetate calcium and sodium chloride are scattered in about 60ml water, transfer pH to 6.5, make glycocholic acid become NaGC, obtain water with sodium hydroxide solution; About 50 ℃, water is under agitation added in the oil phase,, make to reach balance rapidly, obtain microemulsion, filter, add water to 100ml by 1 circulation of homogenizer 400Bar homogenizing, embedding, sterilization is promptly.
Embodiment 5:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 | 1 8 |
| Lecithin MCT sodium ethylene diamine tetracetate calcium glycerol water for injection adds to | 0.1 6 0.005 2 100ml |
Preparation method: 70 ℃ of water-baths lecithin is dissolved among the MCT, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; Sodium ethylene diamine tetracetate calcium and glycerol are dissolved in about 60ml water, obtain water; About 60 ℃, water is under agitation added in the oil phase,, make to reach balance rapidly, obtain microemulsion, filter, add water to 100ml by 1 circulation of homogenizer 600Bar homogenizing, embedding, omnidistance nitrogen current protection, sterilization is promptly.
Embodiment 6:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 lecithin glycocholic acid MCT sodium ethylene diamine tetracetate calcium glucose injection waters add to | 1.5 6 3 0.75 3 0.005 4 100ml |
Preparation method: 70 ℃ of water-baths lecithin is dissolved among the MCT, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; Glycocholic acid, sodium ethylene diamine tetracetate calcium and glucose are scattered in about 60ml water, transfer pH to 8, make glycocholic acid become NaGC, obtain water with sodium hydroxide solution; About 60 ℃, water is under agitation added in the oil phase, continue to stir, obtain microemulsion, filter, add water to 100ml, embedding, omnidistance nitrogen current protection, sterilization is promptly.
Embodiment 7:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 lecithin glycocholic acid MCT glycerol waters for injection add to | 1 1 2 1 2 2 100ml |
Preparation method: 65 ℃ of water-baths lecithin is dissolved among the MCT, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; Glycocholic acid and glycerol are scattered in about 60ml water, transfer pH to 8, make glycocholic acid become NaGC, obtain water with sodium hydroxide solution; About 70 ℃, water is under agitation added in the oil phase,, make to reach balance rapidly, obtain microemulsion, filter, add water to 100ml by 1 circulation of homogenizer 500Bar homogenizing, embedding, omnidistance nitrogen current protection, sterilization is promptly.
Embodiment 8:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 lecithin MCT sodium ethylene diamine tetracetate calcium glycerol waters for injection add to | 1 8 1 4 0.005 2 100ml |
Preparation method: 60 ℃ of water-baths lecithin is dissolved among the MCT, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; Sodium ethylene diamine tetracetate calcium and glycerol are scattered in about 60ml water, transfer pH to 7, obtain water with sodium hydroxide solution; About 60 ℃, water is under agitation added in the oil phase, continue to stir, obtain microemulsion, filter, add water to 100ml, embedding, omnidistance nitrogen current protection, sterilization is promptly.
Embodiment 9:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 lecithin deoxycholic acid MCT sodium ethylene diamine tetracetate calcium chloride injection waters add to | 1 7 1.5 0.1 5 0.005 0.8 100ml |
Preparation method: 60 ℃ of water-baths lecithin is dissolved among the MCT, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; Deoxycholic acid, sodium ethylene diamine tetracetate calcium and sodium chloride are scattered in about 60ml water, transfer pH to 7.5, make deoxycholic acid become sodium deoxycholate, obtain water with sodium hydroxide solution; About 60 ℃, water is under agitation added in the oil phase, continue to stir, obtain microemulsion, filter, add water to 100ml, embedding, omnidistance nitrogen current protection, sterilization is promptly.
Embodiment 10:
Composition prescription:
| Component | Consumption (gram) |
| 2,6-diisopropyl phenol Solutol HS 15 lecithin glycocholic acid MCT sodium ethylene diamine tetracetate calcium glycerol | 1 3 3 0.75 4 0.005 2 |
| Water for injection adds to | 100ml |
Preparation method: 60 ℃ of water-baths lecithin is dissolved among the MCT, adds Solutol HS 15,2, the 6-diisopropyl phenol stirs, and obtains oil phase; Glycocholic acid, sodium ethylene diamine tetracetate calcium and glycerol are scattered in about 60ml water, transfer pH to 7, make glycocholic acid become NaGC, obtain water with sodium hydroxide solution; About 60 ℃, water is under agitation added in the oil phase, continue to stir, obtain microemulsion, filter, add water to 100ml, embedding, omnidistance nitrogen current protection, sterilization is promptly.
Test example 1: the mensuration of particle diameter and zeta current potential
Get and to inject the test cup by the about 2ml of micro emulsion composition of embodiment preparation, pass through Nicomp
TM3 80ZLS particle size determination instrument (U.S. PSS company) are measured the mean diameter and the zeta current potential of particle, the results are shown in Table 1
Table 1 mean diameter and zeta potential measurement result
| Sample | Mean diameter (nm) | Zeta-current potential (mV) |
| Embodiment 1 | 11.3 | -5.82 |
| Embodiment 2 | 25.8 | -3.67 |
| Embodiment 3 | 8.2 | -2.65 |
| Embodiment 4 | 88.2 | -4.02 |
| Embodiment 5 | 45.8 | -2.05 |
| Embodiment 6 | 46.5 | -2.65 |
| Embodiment 7 | 36.8 | -3.91 |
| Embodiment 8 | 48.5 | -3.64 |
| Embodiment 9 | 14.5 | -3.12 |
| Embodiment 10 | 69.7 | -2.71 |
The result shows that each microemulsion is less than the transparent of 100nm and littlely is with opalescent solution.
Test example 2: patent 00809224.9 embodiment 1 described preparation of compositions
Surfactant 0.5g pool Luo Samu 407,4g pool Luo Samu 188,1g Solutol HS 15 are added in the 80g injection pure water, make dissolving.Under agitation dropwise with 1g 2, the 6-diisopropyl phenol adds in the aforementioned solution, continue stirring until and form single phase, add 2.08g glycerol, regulate to wait and ooze, do not add the injection water to 100ml, an amount of sodium hydroxide is transferred pH to 7.4, and the filter of crossing 0.22 micron filters, and the solution of gained is packed into fill in the nitrogen ampoule, sealing, promptly.
Test example 3: the mensuration of aqueous phase free drug concentration
Bag filter was boiled 5 minutes, after about 60 ℃ of distilled water rinsing 2min, one end is tightened with rope, the microemulsion 1.0ml that packs into inserts in the tool plug cillin bottle that 2.5% glycerine water solution 5ml is housed, and covers tight stopper, put in 25 ℃ the water-bath and dialyse, take out after 24 hours, solution filters through microporous filter membrane in the bottle, as need testing solution.With 2,6-diisopropyl phenol raw material is a reference substance, adds methanol and prepares reference substance solution simultaneously, with reference to 2, method under the 6-diisopropyl phenol national drug standards assay item is carried out assay (the results are shown in Table 2) with high performance liquid chromatography, and chromatographic condition is as follows:
Diamonsil
C18 chromatographic column (5 μ m, 250 * 4.6mm); Mobile phase is methanol-acetonitrile-water (60: 15: 25) (adding 0.01% triethylamine mixing); The detection wavelength is 280nm; Sample size 20 μ l.
The measurement result of table 2 aqueous phase free drug concentration
| Sample | Aqueous phase free drug concentration (μ g/ml) |
| Embodiment 1 | 19 |
| Embodiment 2 | 45 |
| Embodiment 3 | 34 |
| Embodiment 4 | 25 |
| Embodiment 5 | 40 |
| Embodiment 6 | 17 |
| Embodiment 7 | 50 |
| Embodiment 8 | 31 |
| Embodiment 9 | 35 |
| Embodiment 10 | 43 |
| Patent 00809224.9 embodiment 1 | 105 |
The result shows, gained microemulsion aqueous phase 2 of the present invention, and 6-diisopropyl phenol concentration is much smaller than 2, and (room temperature is about the saturated concentration of 6-diisopropyl phenol in water: 124 μ g/ml), help realizing 2, the painlessization administration of 6-diisopropyl phenol.And patent 00809224.9 embodiment 1 described compositions microemulsion aqueous phase dissociates 2, and 6-diisopropyl phenol concentration is unfavorable for 2 then up to 105 μ g/ml, the painlessization administration of 6-diisopropyl phenol.
Test example 4: hemolytic test (document 3: " technological guidance's principle of chemicals zest and hemolytic research " [S]. Beijing: State Food and Drug Administration's medicine is evaluated the center)
The preparation of 2% red blood cell suspension: get the about 10ml of Sanguis Leporis seu oryctolagi in the rabbit auricular vein, put into the conical flask jolting 10 minutes that contains bead, remove Fibrinogen.Add the about 10 times of amounts of 0.9% sodium chloride solution, shake up, 3000 rev/mins centrifugal 5 minutes, remove supernatant, sedimentary erythrocyte reuse 0.9% sodium chloride solution washs 2～3 times as stated above, does not show red to supernatant, centrifugal, supernatant discarded night, promptly get erythrocyte.Get the 2ml erythrocyte, be made into the suspension of 100ml 2% with 0.9% sodium chloride solution.
Get 7 of clean tube, be numbered, 1-5 number pipe be for the test sample pipe, manages positive control tube No. 6, manages negative control tube No. 7, by adding 2% red cell suspension, 0.9% sodium chloride solution, distilled water, microemulsion shown in the table 3 successively, mixing.Immediately test tube is put incubation in 37 ℃ ± 0.5 ℃ the water-bath, beginning was observed 1 time every 15 minutes, after 1 hour, observed 1 time every 1 hour, observed altogether 3 hours, and comparative sample pipe and positive control, negative control pipe have judged whether the haemolysis generation.If the solution in the test is clear and bright redness, the pipe end, is acellular residual or have a small amount of erythrocyte residual, and showing has haemolysis to take place; All sink as erythrocyte, supernatant liquid achromatism and clarity shows that no haemolysis takes place.If in the solution brownish red or rufous flocculent deposit are arranged, do not disperse after the jolting, showing has red blood cell condensation to take place.If any the phenomenon of red blood cell condensation, can further judge it is true cohesion or pseudo agglutination by purgation.If condensation product again can homodisperse after test tube vibration, or condensation product is placed on the microscope slide, drip 2 0.9% sodium chloride solutions at the coverslip edge, putting microscopically observes, the cohesion erythrocyte can be pseudo agglutination by the person of breaking up, if condensation product is not shaken diffusing or be not true cohesion by the person of breaking up on slide.
When the negative control pipe does not have haemolysis and cohesion generation, when the positive control pipe has haemolysis to take place,, then tried thing and can be injected use if haemolysis and cohesion did not take place in 3 hours the solution that is tried in the property management; If tried solution in the property management in 3 hours, takes place haemolysis and (or) condense, then tried thing and should not be injected use.(experimental result sees Table 3)
Table 3 test sample pipe and composition table positive, negative tube
| The test tube numbering | 1 | 2 | ?3 | 4 | 5 | 6 | 7 |
| 2% red blood cell suspension (ml), 0.9% sodium chloride solution (ml) distilled water is tried thing (ml) | 2.5 2.4 0.1 | 2.5 2.3 0.2 | ?2.5?2.2?0.3 | 2.5 2.1 0.4 | 2.5 2.0 0.5 | 2.5 2.5 | 2.5 2.5 |
Table 4 hemolytic experiment result
| Sample | The haemolysis situation |
| Positive control | +++++ |
| Negative control | - |
| Embodiment 1 | - |
| Embodiment 2 | - |
| Embodiment 3 | - |
| Embodiment 4 | - |
| Embodiment 5 | - |
| Embodiment 6 | - |
| Embodiment 7 | - |
| Embodiment 8 | - |
| Embodiment 9 | - |
| Embodiment 10 | - |
| Patent 00809224.9 embodiment 1 | ++++ |
The result shows that a large amount of erythroprecipitins is arranged at gained microemulsion sample cell of the present invention and negative control test tube bottom, the upper strata does not have clear and bright redness, illustrate and all do not cause haemolysis, and patent 00809224.9 embodiment, 1 gained microemulsion and positive control test tube bottom have only a spot of erythroprecipitin, the upper strata is clear and bright redness, illustrates that patent 00809224.9 embodiment, 1 gained microemulsion and positive control have haemolysis to take place.
Claims (30)
1. intravenous anesthetic 2, the 6-diisopropyl phenol microemulsion composition is characterized in that, said composition contains:
A) 2, the 6-diisopropyl phenol;
b)Solutol?HS?15；
C) oil for injection;
D) phospholipid; With
E) other water compositions.
2. according to the described micro emulsion composition of claim 1, it is characterized in that described compositions also contains cholate.
3. according to the described micro emulsion composition of claim 1, it is characterized in that described 2, the amount of 6-diisopropyl phenol is 1-2%.
4. according to the described micro emulsion composition of claim 3, it is characterized in that described 2, the amount of 6-diisopropyl phenol is 1%.
5. according to the described micro emulsion composition of claim 1, it is characterized in that the amount of described Solutol HS15 is 1-12%.
6. according to the described micro emulsion composition of claim 5, it is characterized in that the amount of described Solutol HS15 is 3-8%.
7. according to the described micro emulsion composition of claim 1, it is characterized in that described oil for injection is selected from synthetic or natural fatty acid, fatty acid triglycercide or their mixture.
8. according to the described micro emulsion composition of claim 7, it is characterized in that described fatty acid triglycercide is selected from medium chain triglyceride, soybean oil or their mixture.
9. according to the described micro emulsion composition of claim 8, it is characterized in that described fatty acid triglycercide is a medium chain triglyceride.
10. according to the described micro emulsion composition of claim 1, it is characterized in that the amount of described oil for injection is 1-7%.
11., it is characterized in that the amount of described oil for injection is 3-6% according to the described micro emulsion composition of claim 10.
12., it is characterized in that described phospholipid is selected from Ovum Gallus domesticus Flavus lecithin, soybean lecithin or their mixture according to the described micro emulsion composition of claim 1.
13., it is characterized in that the amount of described phospholipid is 0.1-5% according to the described micro emulsion composition of claim 1.
14., it is characterized in that the amount of described phospholipid is 1-3% according to the described micro emulsion composition of claim 13.
15., it is characterized in that described cholate is selected from pharmaceutically acceptable salt class a kind of of glycocholic acid, deoxycholic acid or its mixture according to the described micro emulsion composition of claim 2.
16., it is characterized in that the amount of described cholate is 0.1-1.5% according to the described micro emulsion composition of claim 2.
17., it is characterized in that the amount of described cholate is 0.2-1% according to the described micro emulsion composition of claim 16.
18., it is characterized in that described other water compositions are selected from any one or a few in the acceptable isoosmotic adjusting agent of pharmacy, pH regulator agent, metal ion chelation agent, the antioxidant according to the described micro emulsion composition of claim 1.
19., it is characterized in that the particle diameter of described microemulsion is less than 100nm according to the described micro emulsion composition of claim 1.
20. according to the described micro emulsion composition of claim 1, it is characterized in that, described compositions be appearance transparent and little be with opalescent.
21., it is characterized in that described compositions is thermodynamically stable according to the described micro emulsion composition of claim 1.
22., it is characterized in that described compositions is used for intravenous injection according to the described micro emulsion composition of claim 1.
23., it is characterized in that described compositions is that blood plasma is isoosmotic according to the described micro emulsion composition of claim 1.
24., it is characterized in that described isoosmotic adjusting agent is selected from one or more in glucose, glycerol or the sodium chloride according to the described micro emulsion composition of claim 18.
25., it is characterized in that the pH of described compositions is 5-8 according to the described micro emulsion composition of claim 1.
26., it is characterized in that described pH regulator agent is selected from one or more in sodium hydroxide or hydrochloric acid or its esters according to the described micro emulsion composition of claim 18.
27., it is characterized in that described pH regulator agent is sodium hydroxide or hydrochloric acid according to the described micro emulsion composition of claim 26.
28., it is characterized in that described metal ion chelation agent is selected from one or more in ethylenediaminetetraacetic acid and its esters according to the described micro emulsion composition of claim 18.
29., it is characterized in that described antioxidant is selected from one or more in vitamin E, vitamin C, sodium sulfite, sodium thiosulfate or the L-cysteine according to the described micro emulsion composition of claim 18.
30. prepare the method for the described micro emulsion composition of claim 1 to 29, this method comprises:
(1) prepare hydrophobic phase: with 2,6-diisopropyl phenol, Solutol HS 15, phospholipid are dissolved in the oil for injection;
(2) preparation water: optional cholate or its acid group are dissolved in the water with other water compositions, and the adjusting pH value is 5-9;
(3) under agitation, water is slowly added thin aqueous phase, continue to stir, obtain micro emulsion composition; Or by the homogenizer homogenizing, make to reach balance rapidly, obtain micro emulsion composition;
(4) with the suitable method degerming of micro emulsion composition process, promptly.
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| CN2007101698468A CN101411685B (en) | 2007-10-19 | 2007-11-08 | Intravenous anesthetics 2,6-diisopropyl phenol microemulsion composition and method of making the same |
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| CN200710047269.5 | 2007-10-19 | ||
| CN200710047269 | 2007-10-19 | ||
| CN2007101698468A CN101411685B (en) | 2007-10-19 | 2007-11-08 | Intravenous anesthetics 2,6-diisopropyl phenol microemulsion composition and method of making the same |
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| CN101411685B true CN101411685B (en) | 2011-04-20 |
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| CN101791291B (en) * | 2010-04-02 | 2011-12-28 | 徐州医学院 | Sevoflurane venous microemulsion and preparation method thereof |
| CN103768055B (en) * | 2012-10-26 | 2015-11-25 | 上海医药工业研究院 | Injection etomidate composition and method of making the same |
| CN104288101A (en) * | 2013-07-16 | 2015-01-21 | 天津迈迪瑞康生物医药科技有限公司 | A fat composition used for injection, a preparing method thereof and uses of the fat composition |
| CN104288130A (en) * | 2013-07-16 | 2015-01-21 | 天津迈迪瑞康生物医药科技有限公司 | A propofol composition used for injection, a preparing method thereof and uses of the propofol composition |
| CN104706585A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Vinorelbine bitartrate fat emulsion concentrated solution, preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1177922A (en) * | 1995-03-17 | 1998-04-01 | 曾尼卡有限公司 | Oil in water emulsions containing 2, 6 -diisopropyl phenic and ehtylenedinamine-tetra acetic salt |
| CN1356896A (en) * | 1999-06-21 | 2002-07-03 | 健一制药株式会社 | Anesthetic compsn. for intravenous injection comprising propofol |
| CN1359677A (en) * | 2000-12-20 | 2002-07-24 | 安福星制药公司 | Preparation of propofol with enhanced bacteria inhibition |
| CN1430503A (en) * | 2000-05-25 | 2003-07-16 | 阿斯特拉曾尼卡有限公司 | O/W emulsion |
| CN1917858A (en) * | 2004-02-13 | 2007-02-21 | 生物药效率有限公司 | A microemulsion preparation of high concentration propofol for anesthetic uses |
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2007
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1177922A (en) * | 1995-03-17 | 1998-04-01 | 曾尼卡有限公司 | Oil in water emulsions containing 2, 6 -diisopropyl phenic and ehtylenedinamine-tetra acetic salt |
| CN1356896A (en) * | 1999-06-21 | 2002-07-03 | 健一制药株式会社 | Anesthetic compsn. for intravenous injection comprising propofol |
| CN1430503A (en) * | 2000-05-25 | 2003-07-16 | 阿斯特拉曾尼卡有限公司 | O/W emulsion |
| CN1359677A (en) * | 2000-12-20 | 2002-07-24 | 安福星制药公司 | Preparation of propofol with enhanced bacteria inhibition |
| CN1917858A (en) * | 2004-02-13 | 2007-02-21 | 生物药效率有限公司 | A microemulsion preparation of high concentration propofol for anesthetic uses |
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