CN103768055A - Etomidate composition for injection and preparation method thereof - Google Patents
Etomidate composition for injection and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an etomidate composition for injection. The etomidate composition is characterized by comprising a) etomidate, b) solutol HS 15 and any phospholipid, c) oil for injection and d) a pharmacy acceptable auxiliary material. The invention further discloses a preparation method for the etomidate composition for injection. According to the invention, the particle diameter of the etomidate composition for injection is less than 100 nm, the appearance is transparent, the pH value is 5 to 8, and the composition can be preserved at room temperature, cannot cause hemolysis, can be supplied for injection dosing, and is used of anesthesia induction and maintenance.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of injection etomidate composition and method of making the same.
Background technology
Etomidate (structure is shown in formula 1) is non-barbiturates intravenous anesthesia derivant, its action intensity is respectively 4 times and 12 times of penthiobarbital of barbital sodium, and general anesthesia induction is fast, reviving, recovering after administration is also fast, after emergence, no longer there are drowsiness, dizzy and other untoward reaction, and have the effect of certain resisting emesis, be therefore widely used.It is liquid drugs injection and the fat milk injection etc. of solvent that etomidate has aqueous solution of propylene glycol.Aqueous injection, because injection osmotic pressure is high, usually there will be the side effect such as injection site pain and muscular tremor, Postoperative Intravenous inflammation, thrombophlebitis.
Meanwhile, in etomidate liquid drugs injection, add propylene glycol as cosolvent, and the safety range of taking in for human body propylene glycol, both at home and abroad all without clearly stipulating.Abroad since last century the '30s so far, the safety of propylene glycol is conducted in-depth research, accumulated a large amount of data.Zhang Guangjie etc., have carried out the research of external hemolytic to propylene glycol, result shows: propylene glycol solution can cause rabbit and human red blood cell haemolysis, and some salt can suppress the haemolysis of propylene glycol.As added the sodium chloride of 0.46-0.49% or 0.9% (W/V) in the propylene glycol of 5-30% (V/V), can prevent rabbit erythrocyte hemolysis; In the propylene glycol of 5-40% (V/V), add the sodium chloride of 0.37-0.41% (W/V) can prevent human red blood cell haemolysis.When propylene glycol concentration >=50% (V/V), add sodium chloride can not prevent haemolysis.Result of study shows in vivo, rabbit single intravenous injection gives propylene glycol 4-5ml/kg, tubular and the kidney decolouring of visible haemolysis, hemoglobin (Zhang Guangjie, pharmaceutic adjuvant application technology [M]. Beijing: Chinese Medicine science and technology publishing house, 2002.61-62).
Etomidate fatty emulsion injection has alleviated the side effect such as injection site pain and muscular tremor, Postoperative Intravenous inflammation, thrombophlebitis compared with liquid drugs injection, but fat milk size ratio is larger, likely causes capillary embolism.For example, patent application CN 02112797.2 uses fat emulsion composition technology to prepare the injection-used fat emulsion of etomidate, in said composition, contain soybean oil, Ovum Gallus domesticus Flavus lecithin, glycerol, said composition particle diameter is large, outward appearance is opaque, cannot carry out the inspection of injection visible foreign matters, in injection, may cause phlebitis, pulmonary arteritis as contained foreign body, and the position that microgranule stops up easily occurs in brain, kidney, liver or optical fundus, thereby cause the downright bad or damage in various degree of these positions.Show this preparation unstable (referring to experimental example 3 of the present invention) through frozen process experiment in addition, this technology is unfavorable for the raising of preparation stability.
Summary of the invention
Stronger for existing etomidate compositions injection site irritation, or poor stability, the shortcoming that cannot carry out visible foreign matters inspection, the invention provides a kind of new injection etomidate compositions, described compositions reduces greatly compared with fat milk particle diameter, and stability strengthens.The present invention provides the preparation method of described compositions simultaneously.
Therefore, on the one hand, the invention provides a kind of injection etomidate compositions, it is characterized in that described compositions contains:
A) etomidate;
B) HS15 (Solutol HS 15) and optional phospholipid;
C) oil for injection; With
D) the acceptable adjuvant of pharmacy.
The emulsifying agent Solutol HS 15 using in the present invention, is researched and developed by BASF AG, meets the standard of modern efficient solubilizing agents, can use high temperature hot pressing sterilizing, and its solution viscosity is low, is suitable for drug administration by injection.And there is the low haemolysis of low histamine release, under high concentration, still maintain low viscosity, thereby realize painless administration; Have can with Common Preservatives compatibility, preparation keeps the feature of stability.Solutol HS 15 is by injectable drug application verification at present.These product have been incorporated in Deutscher Arzneibucs, in European Pharmacopoeia and American Pharmacopeia.
According to the present invention one preferred embodiment the amount of described HS15 can be 0.5%～12% (w/v), preferably 0.5%～5% (w/v), more preferably 0.5%～1.5%.
According to the present invention one preferred embodiment, the amount of described etomidate can be 0.05-0.6% (w/v), preferably 0.2% (w/v).
According to the present invention one preferred embodiment, described phospholipid is for example Ovum Gallus domesticus Flavus lecithin, soybean lecithin or other injection phospholipid or their mixture.
The amount of described phospholipid can be 0.1%～5% (w/v), preferably 0.1%～2% (w/v), more preferably 0.1%～0.5% (w/v).
According to the present invention, one preferred embodiment, described oil for injection can be selected from those oils for injection higher to etomidate affinity, can well etomidate be dissolved, make etomidate be not easy to leak in water, for example, for synthetic or natural fatty acid, fatty acid triglycercide, or other injectables oil or their mixture.Wherein fatty acid triglycercide can be selected from medium chain triglyceride, soybean oil or other injectables oil or their mixture, is preferably medium chain triglyceride (MCT).
The amount of described oil for injection can be 0.1%～5% (w/v), preferably more preferably 0.5%～2% (w/v) of 0.5%～3% (w/v).
According to the present invention one preferred embodiment, the acceptable adjuvant of described pharmacy can be any one or a few in isoosmotic adjusting agent, pH adjusting agent, metal ion chelation agent.
Described isoosmotic adjusting agent can be selected from one or more in glucose, glycerol, sodium chloride or other injection isoosmotic adjusting agent.
The amount of described isoosmotic adjusting agent can be 0.5%～6% (w/v).
Described pH adjusting agent can be selected from one or more in sodium hydroxide, hydrochloric acid and other injectables pH adjusting agent or its esters, is preferably sodium hydroxide or hydrochloric acid.
The amount of described pH adjusting agent can be 0%～1% (w/v).
Described metal ion chelation agent can be selected from one or more in ethylenediaminetetraacetic acid and its esters.The amount of described metal ion chelation agent can be 0%～0.1% (w/v).
According to the present invention one preferred embodiment, the pH of described injection etomidate compositions is 5-8.
According to the present invention one preferred embodiment the particle diameter of described injection etomidate compositions is less than 100nm conventionally, appearance transparent, micro-band opalescence, and be thermodynamically stable.Compositions of the present invention can be used for intravenous injection.
According to the present invention one preferred embodiment, described injection etomidate compositions is that blood plasma etc. oozes.
On the other hand, the invention provides a kind of method of preparing above-mentioned injection etomidate compositions, described method comprises:
(1) etomidate, HS15 and optional phospholipid and other fat-soluble adjuvant are dissolved in oil for injection;
(2) acceptable water solublity pharmacy adjuvant is dissolved in water for injection;
(3) water is added in oil phase, add water to full dose, obtain composition solution;
(4) by composition solution embedding, sterilizing, to obtain final product.
The compositions particle diameter that this preparation method forms is less than 100nm, appearance transparent, and pH value is 5-8, can room temperature preserves, and can not cause haemolysis, can supply drug administration by injection, for the induction of anaesthetizing and maintain.
Of the present invention containing etomidate can be used for intravenous injection the advantage of anesthetics compositions be:
1, use injectable adjuvant, safe.
2, prepared compositions is transparent, micro-solution with opalescence, and particle diameter is less than 100nm, and said composition is thermodynamic stable system, storage temperature is required low, can high temperature hot pressing sterilizing; Said composition can be carried out the inspection of injection visible foreign matters, to guarantee the safe handling of injection; Said composition particle diameter is little, can not cause thromboembolism;
4. said composition can not cause the generation of haemolysis.
5. said composition freeze-thaw stability is good.
Accompanying drawing explanation
Fig. 1 is the hemolytic test phenomenon of the injection etomidate compositions for preparing of embodiment 1.Wherein managing 1-3 is test sample pipe, 4 positive control tube, and 5 negative control tube, 6 is test sample control tube.
The specific embodiment
In the following example, provide several injection etomidate compositionss, its preparation method and some experimentation contents by aforementioned summary of the invention, 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 is only for describing specific embodiment, and be not limitation of the invention.
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, hydrochloric acid and sodium hydroxide regulate pH to 6-8, filter, and embedding, sterilizing, to obtain final product.
Composition prescription:
Preparation method:
Under heating condition, MCT and Solutol HS 15 are mixed, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Continue to stir lower adding water and add to mutually in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Continue to stir lower adding water and add to mutually in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, with the hydrochloric acid 0.002ml adjusting pH to 6 of 0.1mol/L, filter, embedding, sterilizing, to obtain final product.
Embodiment 7
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, add glycine 1.0g, with appropriate sodium hydroxide adjusting pH to 6, filter, embedding, sterilizing, to obtain final product.
Embodiment 8
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, with the hydrochloric acid 0.009ml adjusting pH to 5 of 0.1mol/L, filter, embedding, sterilizing, to obtain final product.
Embodiment 9
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 10
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, with the sodium hydroxide 0.009ml adjusting pH to 7 of 0.1mol/L, filter, embedding, sterilizing, to obtain final product.
Embodiment 11
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, with the sodium hydroxide 0.09ml adjusting pH to 8 of 0.1mol/L, filter, embedding, sterilizing, to obtain final product.
Embodiment 12
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 13
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 14
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 15
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 16
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in soybean oil and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 17
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 18
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 19
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in soybean oil and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 20
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 21
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 22
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 23
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 24
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 25
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 26
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 27
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 28
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 29
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 30
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 31
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Solutol HS 15, add etomidate to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 1
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Tween 80, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 2
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Tween 80, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 3
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and Tween 80, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 4
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and PLURONICS F87, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 5
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and PLURONICS F87, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 6
Composition prescription:
Preparation method:
Under heating condition, phospholipid is dissolved in MCT and PLURONICS F87, add etomidate, glycerol to stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Under continuing to stir, water is added in oil phase, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Experimental example 1: the mensuration of particle diameter
Get the injection etomidate compositions of preparing by the embodiment of the present invention, and listing product Eto-lipuro (etomidate aqueous injection) and the about 2ml injection of Fu Erli (Etomidate fatty emulsion injection) test cup, Nicomp passed through
tM380ZLS particle size determination instrument (PSS company of the U.S.) is measured mean diameter, the results are shown in Table 1:
Table 1: mean diameter measurement result
| Sample | Mean diameter (nm) |
| |
41.4 |
| |
59.2 |
| |
41.3 |
| |
42.44 |
| |
41.89 |
| |
42.02 |
| Embodiment 7 | 41.2 |
| Embodiment 8 | 42.3 |
| Embodiment 9 | 41.1 |
| Embodiment 10 | 43.2 |
| Embodiment 11 | 43.9 |
| Embodiment 12 | 45.1 |
| Embodiment 13 | 43.1 |
| Embodiment 14 | 55.9 |
| Embodiment 15 | 56.03 |
| Embodiment 16 | 77.5 |
| Embodiment 17 | 47.8 |
| Embodiment 18 | 48.97 |
| Embodiment 19 | 87.4 |
| Embodiment 20 | 43.04 |
| Embodiment 21 | 43.5 |
| Embodiment 22 | 44.1 |
| Embodiment 23 | 41.03 |
| Embodiment 24 | 41.2 |
| Embodiment 25 | 43.03 |
| Embodiment 26 | 42.97 |
| Embodiment 27 | 40.98 |
| Embodiment 28 | 41.5 |
| Embodiment 29 | 56.03 |
| Embodiment 30 | 55.8 |
| Embodiment 31 | 57.3 |
| Comparative example 4 | 387.4 |
| Comparative example 5 | 356.02 |
| Comparative example 6 | 345.2 |
| Eto-lipuro | 305.1 |
| Fu Erli | 247.4 |
Result shows, each injection etomidate compositions that the embodiment of the present invention makes is particle diameter and is less than the transparent of 100nm and the solution with opalescence, and particle diameter is less, can reduce the risk of blood thromboembolism.And the particle diameter of Eto-lipuro and Fu Erli is more than 100nm, particle diameter is large, outward appearance is opaque, cannot carry out the inspection of injection visible foreign matters, in injection, contain foreign body and may cause phlebitis, pulmonary arteritis, and the position that microgranule stops up easily occurs in brain, kidney, liver or optical fundus, thereby cause the downright bad or damage in various degree of these positions.Comparative example 4-6, shows that PLURONICS F87 is not suitable as the emulsifying agent use of the present composition.Embodiment 29-31 compositions, keeps the amount of oil for injection constant, increases the consumption of phospholipid, reduces the consumption of Solutol HS 15, the particle diameter no significant difference of each compositions simultaneously.Result shows, under the identical condition of oil for injection consumption, phospholipid add the consumption that can reduce total emulsifiers.
Experimental example 2: haemolysis and agglutination test
The preparation of 2% red blood cell suspension: get the about 10ml of Sanguis Leporis seu oryctolagi in rabbit auricular vein, put into containing the conical flask jolting of bead 10 minutes, remove Fibrinogen.Add approximately 10 times of amounts of 0.9% sodium chloride solution, shake up, 1500 revs/min centrifugal 5 minutes, abandoning supernatant, obtains erythrocyte.Get 2ml erythrocyte, be mixed with the red blood cell suspension of 100ml 2% with 0.9% sodium chloride solution.
Each prescription is got 6 of clean tube, be numbered, 1-3 test tube is the test sample of embodiment of the present invention 1-27, manage positive control tube No. 4, manage negative control tube No. 5, by adding successively 2% red blood cell suspension, 0.9% sodium chloride solution, distilled water, etomidate compositions shown in table 2, mix.Immediately test tube is put to incubation in the baking oven of 37 ℃ ± 0.5 ℃, totally 3 hours, comparison specimen QC and positive control pipe, negative control pipe, judged whether that haemolysis occurs.If the solution in test is clear and bright redness, it is residual or a small amount of erythrocyte is residual that the pipe end, is acellular, shows to have haemolysis to occur; As erythrocyte all sinks, supernatant liquid achromatism and clarity, though or supernatant coloured clear and bright, 1,2, No. 3 pipe and No. 5 pipe perusal no significant differences, show to occur without haemolysis.As having brownish red or rufous flocculent deposit in solution, reverse gently 3 times and still do not disperse, show to have red blood cell condensation to occur.If any hemagglutination, can further judge by the following method true cohesion or pseudo agglutination.If condensation product can be uniformly dispersed again after test tube jolting, or condensation product is placed on microscope slide, drip the sodium chloride solution of 2 0.9% at coverslip edge, put micro-Microscopic observation, cohesion erythrocyte can be pseudo agglutination by the person of breaking up, if condensation product is not shaken loose or is not true cohesion by the person of breaking up on slide.
When negative control pipe occurs without haemolysis and cohesion, when positive control pipe has haemolysis to occur, if haemolysis and cohesion did not occur solution in 3 hours in tested property management, tested material can be injected use; If haemolysis and (or) cohesion occurred the solution in tested property management in 3 hours, tested material should not be injected use.
Table 2: test sample and composition table positive, negative tube
Table 3 hemolytic test result
| Sample | 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 | - |
| Embodiment 11 | - |
| Embodiment 12 | - |
| Embodiment 13 | - |
| Embodiment 14 | - |
| Embodiment 15 | - |
| Embodiment 16 | - |
| Embodiment 17 | - |
| Embodiment 18 | - |
| Embodiment 19 | - |
| Embodiment 20 | - |
| Embodiment 21 | - |
| Embodiment 22 | - |
| Embodiment 23 | - |
| Embodiment 24 | - |
| Embodiment 25 | - |
| Embodiment 26 | - |
| Embodiment 27 | - |
| Embodiment 28 | - |
| Embodiment 29 | - |
| Embodiment 30 | - |
| Embodiment 31 | - |
| Comparative example 1 | ± |
| Comparative example 2 | ± |
| Comparative example 3 | ± |
" ± " represents part haemolysis, and "+" represents whole haemolysis, and "-" represents not haemolysis
Result shows, a large amount of erythroprecipitins is arranged at the test sample pipe of embodiment of the present invention 1-27 and negative control pipe bottom, and upper strata without the redness of clear, illustrates and all do not cause haemolysis, can inject use.And haemolysis occurs comparative example 1-3 test sample pipe, show that the compositions of tween 80 easily causes haemolysis.
Experimental example 3: the mensuration of freeze-thaw stability
The injection etomidate compositions that embodiment 1-27 is made and Eto-lipuro, Fu Erli, carry out freeze-thaw stability experiment, totally three circulations, and each circulation comprises placing for-18 ℃ places 2 days for 2 days and 40 ℃, detects outward appearance and particle diameter.
Result is as following table 3:
| Sample | Outward appearance | Particle diameter (nm) |
| |
Transparent micro-band opalescence | 41.3 |
| |
Transparent micro-band opalescence | 59.18 |
| |
Transparent micro-band opalescence | 41.19 |
| |
Transparent micro-band opalescence | 42.56 |
| |
Transparent micro-band opalescence | 41.08 |
| |
Transparent micro-band opalescence | 41.94 |
| Embodiment 7 | Transparent micro-band opalescence | 41.34 |
| Embodiment 8 | Transparent micro-band opalescence | 42.5 |
| Embodiment 9 | Transparent micro-band opalescence | 41.13 |
| Embodiment 10 | Transparent micro-band opalescence | 43.31 |
| Embodiment 11 | Transparent micro-band opalescence | 44.02 |
| Embodiment 12 | Transparent micro-band opalescence | 45.08 |
| Embodiment 13 | Transparent micro-band opalescence | 43.21 |
| Embodiment 14 | Transparent micro-band opalescence | 56.1 |
| Embodiment 15 | Transparent micro-band opalescence | 56.05 |
| Embodiment 16 | Transparent micro-band opalescence | 77.3 |
| Embodiment 17 | Transparent micro-band opalescence | 47.87 |
| Embodiment 18 | Transparent micro-band opalescence | 49.03 |
| Embodiment 19 | Transparent micro-band opalescence | 87.5 |
| Embodiment 20 | Transparent micro-band opalescence | 43.2 |
| Embodiment 21 | Transparent micro-band opalescence | 43.57 |
| Embodiment 22 | Transparent micro-band opalescence | 44.0 |
| Embodiment 23 | Transparent micro-band opalescence | 41.1 |
| Embodiment 24 | Transparent micro-band opalescence | 41.3 |
| Embodiment 25 | Transparent micro-band opalescence | 43.12 |
| Embodiment 26 | Transparent micro-band opalescence | 43.02 |
| Embodiment 27 | Transparent micro-band opalescence | 41.03 |
| Embodiment 28 | Transparent micro-band opalescence | 41.7 |
| Embodiment 29 | Transparent micro-band opalescence | 56.05 |
| Embodiment 30 | Transparent micro-band opalescence | 56.1 |
| Embodiment 31 | Transparent micro-band opalescence | 57.1 |
| Eto-lipuro | Layering | 1560 |
| Fu Erli | Layering | 1240 |
Result shows, the injection etomidate compositions that embodiment 1-27 makes is after frozen process experiment, and outward appearance and particle diameter do not have significant change, and preparation is good to temperature change stability in transportation and use procedure.And Eto-lipuro and Fu Erli, after frozen process experiment, preparation generation layering, and particle diameter enlarges markedly, and preparation is poor to the vary stable of temperature in transportation and use procedure.
Claims (19)
1. injection etomidate compositions, is characterized in that described compositions contains:
A) etomidate;
B) HS15 and optional phospholipid;
C) oil for injection; With
D) the acceptable adjuvant of pharmacy.
2. injection etomidate compositions as claimed in claim 1, the amount that it is characterized in that described etomidate is 0.05-0.6% (w/v), preferably 0.2% (w/v).
3. injection etomidate compositions as claimed in claim 1, the amount that it is characterized in that described HS15 is 0.5%～12% (w/v), preferably 0.5%～5% (w/v), more preferably 0.5%～1.5% (w/v).
4. injection etomidate compositions as claimed in claim 1, is characterized in that described phospholipid is Ovum Gallus domesticus Flavus lecithin, soybean lecithin or its mixture.
5. injection etomidate compositions as claimed in claim 4, the amount that it is characterized in that described phospholipid is 0.1%～5% (w/v), preferably 0.1%～2% (w/v), more preferably 0.1%～0.5% (w/v).
6. injection etomidate compositions as claimed in claim 1, is characterized in that described oil for injection is selected from synthetic or natural fatty acid, fatty acid triglycercide or its mixture.
7. injection etomidate compositions as claimed in claim 1, is characterized in that described fatty acid triglycercide is selected from medium chain triglyceride, soybean oil or its mixture, is preferably medium chain triglyceride.
8. injection etomidate compositions as claimed in claim 1, the amount that it is characterized in that described oil for injection is 0.1%～5% (w/v), preferably 0.5%～3% (w/v), more preferably 0.5%～2% (w/v).
9. injection etomidate compositions as claimed in claim 1, is characterized in that the acceptable adjuvant of described pharmacy is selected from any one or a few in isoosmotic adjusting agent, pH adjusting agent, metal ion chelation agent, water for injection.
10. injection etomidate compositions as claimed in claim 9, is characterized in that described pH adjusting agent is selected from one or more in sodium hydroxide and hydrochloric acid.
11. injection etomidate compositionss as claimed in claim 10, the amount that it is characterized in that described pH adjusting agent is 0%～1% (w/v).
12. injection etomidate compositionss as claimed in claim 9, is characterized in that described isoosmotic adjusting agent is selected from one or more in glucose, glycerol and sodium chloride.
13. injection etomidate compositionss as claimed in claim 12, the consumption that it is characterized in that described isoosmotic adjusting agent is 0.5%～6.0% (w/v).
14. injection etomidate compositionss as claimed in claim 9, is characterized in that described metal ion chelation agent is selected from one or more in ethylenediaminetetraacetic acid and its esters.
15. injection etomidate compositionss as claimed in claim 14, is characterized in that the consumption of described metal ion chelation agent is 0%～0.1% (w/v).
16. injection etomidate compositionss as described in claim 1-15 any one, the pH that it is characterized in that described compositions is 5-8.
17. injection etomidate compositionss as described in claim 1-15 any one, is characterized in that the particle diameter of described compositions is less than 100nm.
18. injection etomidate compositionss as described in claim 1-15 any one, is characterized in that described compositions is that blood plasma etc. oozes.
The method of the injection etomidate compositions described in 19. preparation claim 1-18 any one, is characterized in that described method comprises:
(1) etomidate, HS15 and optional phospholipid and other fat-soluble adjuvant are dissolved in oil for injection;
(2) acceptable water solublity pharmacy adjuvant is dissolved in water for injection;
(3) water is added in oil phase, add water to full dose, obtain composition solution;
(4) by composition solution embedding, sterilizing, to obtain final product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104706587A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Etomidate fat emulsion concentrated solution, preparation method and application thereof |
| CN107049967A (en) * | 2016-12-31 | 2017-08-18 | 辰欣药业股份有限公司 | A kind of Etomidate freeze-dried emulsion and preparation method thereof |
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| CN101032467A (en) * | 2007-04-13 | 2007-09-12 | 西安力邦制药有限公司 | Superregulated long-cycled lipid emulsion carrying medicine reagent for mainline |
| WO2008139313A2 (en) * | 2007-05-14 | 2008-11-20 | Ciriaco Quiroga | Propofol transparent anaesthetic solution with low venous irritation |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1356896A (en) * | 1999-06-21 | 2002-07-03 | 健一制药株式会社 | Anesthetic compsn. for intravenous injection comprising propofol |
| CN1399959A (en) * | 2002-03-25 | 2003-03-05 | 徐州颐华医药科技有限公司 | Etomidate fatty emulsion injection preparation method |
| CN101032467A (en) * | 2007-04-13 | 2007-09-12 | 西安力邦制药有限公司 | Superregulated long-cycled lipid emulsion carrying medicine reagent for mainline |
| WO2008139313A2 (en) * | 2007-05-14 | 2008-11-20 | Ciriaco Quiroga | Propofol transparent anaesthetic solution with low venous irritation |
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| CN104706587A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Etomidate fat emulsion concentrated solution, preparation method and application thereof |
| CN107049967A (en) * | 2016-12-31 | 2017-08-18 | 辰欣药业股份有限公司 | A kind of Etomidate freeze-dried emulsion and preparation method thereof |
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| CN103768055B (en) | 2015-11-25 |
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