CN103768055B - Injection etomidate composition and method of making the same - Google Patents
Injection etomidate composition and method of making the same Download PDFInfo
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Abstract
The present invention discloses a kind of injection etomidate compositions, it is characterized in that described compositions contains: a) etomidate; B) HS15 and optional phospholipid; C) oil for injection; And d) the acceptable adjuvant of pharmacy.The present invention also discloses the preparation method of described injection etomidate compositions.The particle diameter of injection etomidate compositions of the present invention is less than 100nm, appearance transparent, and pH value is 5-8, can preserve by room temperature, can not cause haemolysis, can supply drug administration by injection, for the induction of anaesthetizing 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 of barbital sodium and 12 times of penthiobarbital, and general anesthesia induction is fast, reviving after administration, recover also fast, no longer there are drowsiness, dizzy and other untoward reaction after emergence, and have the effect of certain resisting emesis, be therefore widely used.Etomidate has aqueous solution of propylene glycol to be the liquid drugs injection and fat milk injection etc. of solvent.Aqueous injection is high because of injection osmotic pressure, usually there will be the side effect such as injection site pain and muscular tremor, Postoperative Intravenous inflammation, thrombophlebitis.
Formula 1
Meanwhile, add propylene glycol in etomidate liquid drugs injection as cosolvent, and for the safety range that human body propylene glycol is taken in, both at home and abroad all without clear stipulaties.Abroad from last century the '30s so far, the safety of propylene glycol is conducted in-depth research, have accumulated a large amount of data.Zhang Guangjie etc., carried out the research of hemolysis in vitro 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), rabbit erythrocyte hemolysis can be prevented; The sodium chloride adding 0.37-0.41% (W/V) in the propylene glycol of 5-40% (V/V) can prevent human red blood cell haemolysis.When PG concentration >=50% (V/V), add sodium chloride and then can not prevent haemolysis.Result of study display in vivo, rabbit single intravenous injection gives propylene glycol 4-5ml/kg, the decolouring of visible haemolysis, hemoglobin tubular and kidney (Zhang Guangjie, pharmaceutic adjuvant application technology [M]. Beijing: China Medical Science Press, 2002.61-62).
Etomidate fatty emulsion injection alleviates the side effect such as injection site pain and muscular tremor, Postoperative Intravenous inflammation, thrombophlebitis compared with liquid drugs injection, but fat milk particle diameter is larger, likely causes capillary embolism.Such as, patent application CN02112797.2 uses fat emulsion composition technology to prepare the injection-used fat emulsion of etomidate, containing soybean oil, Ovum Gallus domesticus Flavus lecithin, glycerol in said composition, said composition particle diameter is large, outward appearance is opaque, cannot carry out the inspection of injection visible foreign matters, as caused phlebitis, pulmonary arteritis containing foreign body in injection, and the position of particles holography easily occurs in brain, kidney, liver or optical fundus, thus cause the necrosis in various degree of these positions or damage.Show this preparation instability (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 of visible foreign matters inspection cannot be carried out, the invention provides a kind of new injection etomidate compositions, described compositions comparatively fat milk particle diameter reduces greatly, and stability strengthens.Invention also provides the preparation method of described compositions.
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 (SolutolHS15) and optional phospholipid;
C) oil for injection; With
D) the acceptable adjuvant of pharmacy.
The emulsifying agent SolutolHS15 used in the present invention, is researched and developed by BASF AG, meets the standard of modern efficient solubilizing agent, 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, still maintain low viscosity under high concentration, thus realize painless administration; Have can with Common Preservatives compatibility, preparation keeps the feature of stability.Current SolutolHS15 is by injectable drug application verification.These product are 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 such as Ovum Gallus domesticus Flavus lecithin, soybean lecithin or other injection phosphotide 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, well etomidate can be dissolved, etomidate is made to be not easy to leak in aqueous phase, such as synthesis 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 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 0.5% ~ 3% (w/v) more preferably 0.5% ~ 2% (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 injectable pH adjusting agents 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 usually, appearance transparent, micro-band opalescence, and is 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 is isotonic.
On the other hand, the invention provides a kind of method 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 for water-soluble pharmaceutical adjuvant is dissolved in water for injection;
(3) aqueous phase 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 is formed is less than 100nm, appearance transparent, and pH value is 5-8, can preserve by room temperature, can not cause haemolysis, can supply drug administration by injection, for the induction of anaesthetizing and maintenance.
Of the present invention containing etomidate can be used for intravenous injection the advantage of anesthetics compositions be:
1, use injectable adjuvant, safety is high.
2, prepared compositions is solution that is transparent, micro-band opalescence, and particle diameter is less than 100nm, and said composition is thermodynamic stable system, requires low to storage temperature, can high temperature hot pressing sterilizing; Said composition can carry out the inspection of injection visible foreign matters, to ensure 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 that embodiment 1 prepares.Wherein pipe 1-3 is test sample pipe, and 4 is positive control pipe, and 5 is negative control pipe, and 6 is test sample control tube.
Detailed description of the invention
Several injection etomidate compositions, its preparation method and some experimentation contents is provided by foregoing summary in the following example, but the composition and method of making the same that the place that should be appreciated that the present invention is not limited to this is listed, should also be appreciated that term as used herein only for describing specific embodiment, and be not limitation of the invention.
Embodiment 1
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, hydrochloric acid and sodium hydroxide regulate pH to 6-8, and filter, embedding, sterilizing, to obtain final product.
Embodiment 2
Composition prescription:
Preparation method:
In a heated condition, MCT and SolutolHS15 is mixed, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; To add water under Keep agitation and add to mutually in oil phase, and add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 3
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; To add water under Keep agitation and add to mutually in oil phase, and add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 4
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 5
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 6
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, regulate pH to 6 with the hydrochloric acid 0.002ml of 0.1mol/L, filter, embedding, sterilizing, to obtain final product.
Embodiment 7
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate and stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, add glycine 1.0g, regulate pH to 6 with appropriate sodium hydroxide, filter, embedding, sterilizing, to obtain final product.
Embodiment 8
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate and stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, regulate pH to 5 with the hydrochloric acid 0.009ml of 0.1mol/L, filter, embedding, sterilizing, to obtain final product.
Embodiment 9
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate and stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 10
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate and stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, regulate pH to 7 with the sodium hydroxide 0.009ml of 0.1mol/L, filter, embedding, sterilizing, to obtain final product.
Embodiment 11
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, regulate pH to 8 with the sodium hydroxide 0.09ml of 0.1mol/L, filter, embedding, sterilizing, to obtain final product.
Embodiment 12
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 13
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 14
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 15
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 16
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in soybean oil and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 17
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 18
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 19
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in soybean oil and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 20
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 21
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 22
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 23
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 24
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 25
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 26
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 27
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate and stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 28
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate and stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 29
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate and stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 30
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate and stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Embodiment 31
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and SolutolHS15, adds etomidate and stir, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 1
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and Tween 80, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 2
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and Tween 80, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 3
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and Tween 80, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 4
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and PLURONICS F87, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 5
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and PLURONICS F87, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Comparative example 6
Composition prescription:
Preparation method:
In a heated condition, phospholipid is dissolved in MCT and PLURONICS F87, adds etomidate, glycerol stirs, obtain oil phase; Other adjuvant is dissolved in water for injection; Add in oil phase by aqueous phase under Keep agitation, add water to 100ml, filter, embedding, sterilizing, to obtain final product.
Experimental example 1: the mensuration of particle diameter
Get the injection etomidate compositions prepared by the embodiment of the present invention, and commercialized product Eto-lipuro (etomidate aqueous injection) and Fu Erli (Etomidate fatty emulsion injection) about 2ml inject test cup, pass through Nicomp
tM380ZLS particle size determination instrument (PSS company of the U.S.) measures mean diameter, the results are shown in Table 1:
Table 1: mean diameter measurement result
| Sample | Mean diameter (nm) |
| Embodiment 1 | 41.4 |
| Embodiment 2 | 59.2 |
| Embodiment 3 | 41.3 |
| Embodiment 4 | 42.44 |
| Embodiment 5 | 41.89 |
| Embodiment 6 | 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 obtains is particle diameter and is less than the transparent of 100nm and the solution of band opalescence, and particle diameter is less, can reduce the risk of Blood occlusion.And the particle diameter of Eto-lipuro and Fu Erli is at more than 100nm, particle diameter is large, outward appearance is opaque, the inspection of injection visible foreign matters cannot be carried out, phlebitis, pulmonary arteritis may be caused containing foreign body in injection, and the position of particles holography easily occurs in brain, kidney, liver or optical fundus, thus cause the necrosis in various degree of these positions or damage.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, reduce the consumption of SolutolHS15, the particle diameter no significant difference of each compositions simultaneously.Result shows, under the condition that oil for injection consumption is identical, 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 Sanguis Leporis seu oryctolagi in rabbit auricular vein and be about 10ml, puts into the conical flask jolting 10 minutes containing bead, removing Fibrinogen.Add 0.9% sodium chloride solution about 10 times amount, shake up, 1500 revs/min centrifugal 5 minutes, and abandoning supernatant, obtains erythrocyte.Get 2ml erythrocyte, be mixed with the red blood cell suspension of 100ml2% with 0.9% sodium chloride solution.
Clean tube 6 got by each prescription, be numbered, 1-3 test tube is the test sample of embodiment of the present invention 1-27, No. 4 pipes are positive control pipe, No. 5 pipes are negative control pipe, by adding 2% red blood cell suspension, 0.9% sodium chloride solution, distilled water, etomidate compositions shown in table 2 successively, mixing.Immediately test tube is put incubation in the baking oven of 37 DEG C ± 0.5 DEG C, 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, at the bottom of pipe, acellular residual or a small amount of erythrocyte remains, and shows have haemolysis to occur; As erythrocyte all sinks, supernatant fluid achromatism and clarity, though or supernatant coloured clear and bright, 1,2, No. 3 pipe and No. 5 pipe perusal no significant differences, then show to occur without haemolysis.As having brownish red or rufous flocculent deposit in solution, reversing does not still disperse for 3 times gently, shows to have red blood cell condensation to occur.If any hemagglutination, true cohesion or pseudo agglutination can be judged by the following method further.If condensation product can be uniformly dispersed again after test tube jolting, or condensation product is placed on microscope slide, the sodium chloride solution of 2 0.9% is dripped at coverslip edge, put basis of microscopic observation, cohesion erythrocyte can be pseudo agglutination by the person of breaking up, if condensation product is not shaken and falls apart or be 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 solution, in 3 hours, haemolysis and cohesion does not occur in tested property management, then tested material can inject use; If the solution in tested property management, in 3 hours, haemolysis and (or) cohesion occurs, then tested material should not inject use.
Table 2: test sample and composition table that is 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 non-haemolysis
Result shows, has a large amount of erythroprecipitins bottom the test sample pipe of embodiment of the present invention 1-27 and negative control pipe, and upper strata, without the redness of clear, illustrates and all do not cause haemolysis, can inject use.And comparative example 1-3 test sample pipe, there is haemolysis, show that the compositions of tween 80 easily causes haemolysis.
Experimental example 3: the mensuration of freeze-thaw stability
By injection etomidate compositions obtained for embodiment 1-27 and Eto-lipuro, Fu Erli, carry out freeze-thaw stability experiment, totally three circulations, each circulation comprises-18 DEG C and places 2 days and 40 DEG C of placements 2 days, detection outward appearance and particle diameter.
Result is as following table 3:
| Sample | Outward appearance | Particle diameter (nm) |
| Embodiment 1 | Transparent micro-band opalescence | 41.3 |
| Embodiment 2 | Transparent micro-band opalescence | 59.18 |
| Embodiment 3 | Transparent micro-band opalescence | 41.19 |
| Embodiment 4 | Transparent micro-band opalescence | 42.56 |
| Embodiment 5 | Transparent micro-band opalescence | 41.08 |
| Embodiment 6 | 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 obtains 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 transport 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 transport and use procedure.
Claims (25)
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;
The amount of wherein said etomidate is 0.05-0.6% (w/v); The amount of described HS15 is 0.5% ~ 12% (w/v).
2. injection etomidate compositions as claimed in claim 1, is characterized in that the amount of described etomidate is 0.2% (w/v).
3. injection etomidate compositions as claimed in claim 1, is characterized in that the amount of described HS15 is 0.5% ~ 5% (w/v).
4. injection etomidate compositions as claimed in claim 3, is characterized in that the amount of described HS15 is 0.5% ~ 1.5% (w/v).
5. 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.
6. injection etomidate compositions as claimed in claim 5, is characterized in that the amount of described phospholipid is 0.1% ~ 5% (w/v).
7. injection etomidate compositions as claimed in claim 6, is characterized in that the amount of described phospholipid is 0.1% ~ 2% (w/v).
8. injection etomidate compositions as claimed in claim 7, is characterized in that the amount of described phospholipid is 0.1% ~ 0.5% (w/v).
9. injection etomidate compositions as claimed in claim 1, is characterized in that described oil for injection is selected from synthesis or natural fatty acid, fatty acid triglycercide or its mixture.
10. 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.
11. injection etomidate compositionss as claimed in claim 10, is characterized in that described fatty acid triglycercide is selected from medium chain triglyceride.
12. injection etomidate compositionss as claimed in claim 1, is characterized in that the amount of described oil for injection is 0.1% ~ 5% (w/v).
13. injection etomidate compositionss as claimed in claim 12, is characterized in that the amount of described oil for injection is 0.5% ~ 3% (w/v).
14. injection etomidate compositionss as claimed in claim 13, is characterized in that the amount of described oil for injection is 0.5% ~ 2% (w/v).
15. injection etomidate compositionss as claimed in claim 1, it is characterized in that the acceptable adjuvant of described pharmacy is selected from isoosmotic adjusting agent, pH adjusting agent, metal ion chelation agent, water for injection any one or a few.
16. injection etomidate compositionss as claimed in claim 15, is characterized in that one or more that described pH adjusting agent is selected from sodium hydroxide and hydrochloric acid.
17. injection etomidate compositionss as claimed in claim 16, is characterized in that the amount of described pH adjusting agent is 0% ~ 1% (w/v).
18. injection etomidate compositionss as claimed in claim 15, is characterized in that one or more that described isoosmotic adjusting agent is selected from glucose, glycerol and sodium chloride.
19. injection etomidate compositionss as claimed in claim 18, is characterized in that the consumption of described isoosmotic adjusting agent is 0.5% ~ 6.0% (w/v).
20. injection etomidate compositionss as claimed in claim 15, is characterized in that one or more that described metal ion chelation agent is selected from ethylenediaminetetraacetic acid and its esters.
21. injection etomidate compositionss as claimed in claim 20, is characterized in that the consumption of described metal ion chelation agent is 0% ~ 0.1% (w/v).
22. injection etomidate compositionss as described in any one of claim 1-21, is characterized in that the pH of described compositions is 5-8.
23. injection etomidate compositionss as described in any one of claim 1-21, is characterized in that the particle diameter of described compositions is less than 100nm.
24. injection etomidate compositionss as described in any one of claim 1-21, is characterized in that described compositions is that blood plasma is isotonic.
The method of the injection etomidate compositions described in 25. any one of preparation claim 1-24, 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 for water-soluble pharmaceutical adjuvant is dissolved in water for injection;
(3) aqueous phase is added in oil phase, add water to full dose, obtain composition solution;
(4) by composition solution embedding, sterilizing, to obtain final product;
The amount of wherein said etomidate is 0.05-0.6% (w/v); The amount of described HS15 is 0.5% ~ 12% (w/v).
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| 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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|---|---|---|---|---|
| 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 |
| CN101411685A (en) * | 2007-10-19 | 2009-04-22 | 上海医药工业研究院 | Intravenous anesthetics 2,6-diisopropyl phenol microemulsion composition and method of making the same |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101411685A (en) * | 2007-10-19 | 2009-04-22 | 上海医药工业研究院 | Intravenous anesthetics 2,6-diisopropyl phenol microemulsion composition and method of making the same |
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