CN107982215A - A kind of butyrate clevidipine emulsion and preparation method and application - Google Patents
A kind of butyrate clevidipine emulsion and preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of butyrate clevidipine emulsion and preparation method and application.Butyrate clevidipine emulsion of the present invention in phosphatidyl choline (PC), phosphatidyl-ethanolamine (PE) and cholesterol (TC) content to emulsifying agent egg yolk lecithin by carrying out strict regulations, there is stringent control to homogenization pressure in preparation process at the same time, stability of the butyrate clevidipine emulsion during storage and use is improved, is subjected to phenomena such as sample after Frozen-thawed cycled three times does not produce fuel-displaced, demulsification, water-oil separating still.The butyrate clevidipine emulsion preparation process of the present invention is workable, is easy to large-scale production.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of butyrate clevidipine emulsion and preparation method thereof is with answering
With.
Background technology
Peri-operation period refers to an overall process around operation, since patient determines to be treated surgically, is controlled to operation
Treat until basic rehabilitation, includes early period of performing the operation, operation mid-term and postoperative period.Perioperative Patients due to stress, wound,
Pain stimulation after pain, operation wound and postoperative anesthetic effect disappearance, blood pressure can be raised further, particularly with hypertension
Disease needs risk bigger existing for the patient of surgical operation, and data in literature shows that Perioperative Hypertension is clinically relatively conventional,
Patients undergoing cardiac valve replacement of the incidence up to 30~60%, and more than 80%, more than 25% non-cardiac major operation patient can suffer from urgency
Property Perioperative Hypertension, some even occur hypertension emergency (hypertensive crisis, hypertensive encephalopathy, acute left ventricular failure),
Acute hypertension can directly or indirectly cause the increase of patient with operation postoperative complications and the death rate, and therefore, peri-operation period is high
Blood pressure (Perioperative hypertension) and its nursing have been that pendulum is important in face of surgical departments nursery work
Problem, whether Treatment Around Operative Period is appropriate, timely, is directly related to the final result of surgical intervention.Clinical test shows to pass through
The rational use of medicines can be such that patients during peri is steadily depressured, and reduce the appearance of postoperative complications, so that surgical success rate is improved,
Reduce operative mortality rate.
Butyrate clevidipine reduces mean arterial pressure by selective Diastolic arterial blood vessel, reduction systemic vascular resistance,
Without reducing heart filling pressure (preload), on myocardial contractive power and vein blood vessel capacity also without influence.In metabolic pathway also with
It is existing intravenously different with drug for hypertension, it not via liver or (and) kidney, the influence from hepatic and renal function damage, but
Metabolism is undergone in blood and tissue, while will not be accumulated in vivo, so pharmacodynamics and pharmacokinetic advantage are obvious, on Clinical practice
It is gradually reduced for patient's systolic pressure in 15 minutes after Perioperative Hypertension patient medication, medication reaches Stationary Water after 15 minutes
Flat, changes in heart rate is substantially steady in 30 minutes after medication.
Butyrate clevidipine belongs to dihydrogen pyridine derivative, is a kind of calcium channel blocker used for intravenous injection of ultrashort effect,
Blood vessel and cardiac muscle selectivity with height, rapid metabolization is inert matter in vivo.Its is rapid-action, and effect elimination is also fast,
Can ascending-dose accurately control blood pressure.Butyrate clevidipine is almost insoluble in water, soybean oil, median chain triglyceride oil and its
It is readily soluble in his fat oil.Therefore the liquid emulsion of O/W is suitably made.
Since emulsion belongs to thermodynamic unstable system, water-oil separating is also easy to produce in storage and using process.Therefore, it is existing
Still there is an urgent need to provide a kind of to remain stable preparation during storage and use for technology.
The content of the invention
The technical problems to be solved by the invention are to improve butyrate clevidipine emulsion for injection in storage and using process
In stability, be subjected to phenomena such as sample after Frozen-thawed cycled three times does not produce fuel-displaced, demulsification, water-oil separating still.So as to
The present invention provides a kind of butyrate clevidipine emulsion and preparation method thereof.Butyrate clevidipine emulsion of the present invention passes through to emulsifying agent
Egg yolk lecithin carries out strict regulations in phosphatidyl choline (PC), phosphatidyl-ethanolamine (PE) and cholesterol (TC) content, at the same time
There is stringent control in preparation process to homogenization pressure.And the butyrate clevidipine emulsion preparation process operability of the present invention
By force, it is easy to large-scale production.
The present invention adopts the following technical scheme that：
A kind of preparation method of butyrate clevidipine emulsion, the butyrate clevidipine emulsion prescription are as follows：
PC (phosphatidyl choline) content is 65-90% (w/w, similarly hereinafter) in the egg yolk lecithin, is preferably 70-85%,
More preferably 75-80%.
PE (phosphatidyl-ethanolamine) content is 5-20% in the egg yolk lecithin, is preferably 10-18%, more preferably
12-17%.
TC (cholesterol) content is 0.5-2.0% in the egg yolk lecithin, is preferably 1.0-2.0%, more preferably
1.5-2.0%.
On the basis of common knowledge of the art, in above-mentioned egg yolk lecithin PC, PE, TC content each optimum condition, can
To be mutually combined, up to each preferred embodiment of the present invention.
The preparation method of the butyrate clevidipine emulsion includes the following steps：
1) water of recipe quantity is taken, pH value is adjusted to 8~9 with pH adjusting agent, adds edetate, glycerine, stirring
It is uniformly dissolved it；Nitrogen deoxygenation is passed through into water, water temperature controls 50~90 DEG C, and the egg yolk lecithin for adding recipe quantity is cut, and is cut
It is uniformly dispersed to egg yolk lecithin；Water phase is made；Whole process carries out under nitrogen protective condition；
2) fat oil of recipe quantity is taken after 50~90 DEG C of heating make dissolving, adds the butyrate clevidipine, steady of recipe quantity
Determine agent, be uniformly mixed, nitrogen filled protection, system temperature is controlled at 50~90 DEG C, and oil phase is made；
3) gained water is mutually slowly injected into gained oil phase under the conditions of high-speed stirred, colostrum, emulsion temperature control is made in shearing
System is at 50~70 DEG C；
4) under nitrogen protective condition, gained colostrum is subjected to twice homogenization, first is inferior to pressure 40-200bar, homogeneous
1-6 times, second is inferior to pressure 500-1200bar homogeneous 4-10 times；3 μm of filter filterings, inflated with nitrogen, embedding are crossed after homogeneous；Sterilizing；
.
Preferably, first time homogeneous is in pressure 80-150bar, homogeneous 1-6 times, such as 2-3 times, more preferably homogeneous 6 times.
Preferably, second homogeneous is equal 4-9 times in pressure 600-1000bar.
A kind of preferably embodiment of the present invention is that gained colostrum is carried out twice homogenization by step 4), and first is inferior to pressure
80-150bar, homogeneous 6 times, second is inferior to pressure 800bar homogeneous 7 times.
The sterilizing can use this area conventional method, such as 121 DEG C, F0＞ 12 sterilizes.
Further, the fat oil can be soybean oil, median chain triglyceride oil, peanut oil, olive oil, sesame oil, fish oil
One or more in, are preferably soybean oil, the miscella of median chain triglyceride oil, more preferably soybean oil.
Further, the egg yolk lecithin is preferably refined egg yolk lecithin, commercially available to buy.
Further, the edetate is in calcio-disodium edetate, disodium ethylene diamine tetraacetate etc.
One or more, more preferably disodium ethylene diamine tetraacetate.
Further, the dosage of the edetate is 0.002-0.01% (w/w, similarly hereinafter), is preferably
0.005-0.01%.
Further, the stabilizer can be capric acid or its salt, laurate or its salt, myristic acid or its salt, palmitic acid
Or in its salt, palmitoleic acid or its salt, stearic acid or its salt, linoleic acid or its salt, leukotrienes or its salt, oleic acid or its salt etc.
One or more, are preferably enuatrol or oleic acid, more preferably oleic acid.
Further, the dosage of the stabilizer is 0.01-0.06% (w/w, similarly hereinafter), is preferably 0.03-0.06%.
Further, the pH adjusting agent may be selected from phosphate, citrate, acetate, borate, hydrochloric acid, phosphoric acid, hydrogen
Sodium oxide molybdena etc., preferably sodium hydroxide, such as 2% sodium hydroxide solution.
Raw material of the present invention is commercially available to be bought.
Present invention additionally comprises butyrate clevidipine emulsion prepared by the above method.
Present invention additionally comprises application of the above-mentioned butyrate clevidipine emulsion on drug for hypertension is prepared.
Embodiment
Following embodiments are used to illustrate the present invention, but are not limited to the scope of the present invention.It is not specified in embodiment specific
Technology or condition person, carry out according to the described technology of document in the art or condition, or according to product description.It is used
Production firm person is not specified in reagent or instrument, is the conventional products that can be commercially available by regular distributor.
Embodiment 1
A kind of butyrate clevidipine emulsion, its prescription are as follows：
Wherein refined egg yolk lecithin PC contents are 77%, PE contents are 18%, TC contents are 1.1%.
Preparation method includes the following steps：
1st, the fresh water for injection of recipe quantity is taken, adds 2% sodium hydroxide to adjust pH value 9.0, adds ethylenediamine tetra-acetic acid
Sodium, glycerine, stir to dissolve uniformly, and nitrogen deoxygenation is passed through in water, and water temperature controls 75 DEG C, adds the refined yolk ovum of recipe quantity
Phosphatide is sheared to refined egg yolk lecithin and is uniformly dispersed, and whole process is completed in nitrogen protection, as water phase.
2nd, take the butyrate clevidipine of recipe quantity, fat oil after 75 DEG C of heating make dissolving, add recipe quantity soybean oil,
Stability, is uniformly mixed, nitrogen filled protection, Oil-temperature control is at 75 DEG C, as oil phase.
3rd, water is mutually while carry out high speed shear, while being slowly injected into oil phase, colostrum is made in shearing, and emulsion temperature is controlled 60
℃。
4th, under nitrogen guard mode, colostrum is subjected to homogeneous, 80-150bar homogeneous 6 times, 800bar homogeneous 7 times.Cross 3 μ
M filters filter, inflated with nitrogen, embedding.121℃、F0＞ 12 sterilizes.
Embodiment 2
A kind of butyrate clevidipine emulsion, its prescription are as follows：
Refined egg yolk lecithin PC contents are 80%, PE contents are 13%, TC contents are 1.8%.
Preparation method includes the following steps：
1st, the fresh water for injection of recipe quantity is taken, adds 2% sodium hydroxide to adjust pH value 9.0, adds ethylenediamine tetra-acetic acid
Sodium, glycerine, stir to dissolve uniformly, and nitrogen deoxygenation is passed through in water, and water temperature controls 75 DEG C, adds the refined yolk ovum of recipe quantity
Phosphatide is sheared to refined egg yolk lecithin and is uniformly dispersed, and whole process is completed in nitrogen protection, as water phase.
2nd, take the butyrate clevidipine of recipe quantity, fat oil after 75 DEG C of heating make dissolving, add recipe quantity soybean oil,
Stability, is uniformly mixed, nitrogen filled protection, Oil-temperature control is at 75 DEG C, as oil phase.
3rd, water is mutually while carry out high speed shear, while being slowly injected into oil phase, colostrum is made in shearing, and emulsion temperature is controlled 60
℃。
4th, under nitrogen guard mode, colostrum is subjected to homogeneous, 80-150bar homogeneous 6 times, 800bar homogeneous 7 times.Cross 3 μ
M filters filter, inflated with nitrogen, embedding.121℃、F0＞ 12 sterilizes.
Embodiment 3
A kind of butyrate clevidipine emulsion, its prescription are as follows：
Wherein refined egg yolk lecithin PC contents are 70%, PE contents are 20%, TC contents are 0.8%.
Preparation method includes the following steps：
1st, the fresh water for injection of recipe quantity is taken, adds 2% sodium hydroxide to adjust pH value 9.0, adds ethylenediamine tetra-acetic acid
Sodium, glycerine, stir to dissolve uniformly, and nitrogen deoxygenation is passed through in water, and water temperature controls 75 DEG C, adds the refined yolk ovum of recipe quantity
Phosphatide is sheared to refined egg yolk lecithin and is uniformly dispersed, and whole process is completed in nitrogen protection, as water phase.
2nd, take the butyrate clevidipine of recipe quantity, fat oil after 75 DEG C of heating make dissolving, add recipe quantity soybean oil,
Stability, is uniformly mixed, nitrogen filled protection, Oil-temperature control is at 75 DEG C, as oil phase.
3rd, water is mutually while carry out high speed shear, while being slowly injected into oil phase, colostrum is made in shearing, and emulsion temperature is controlled 60
℃。
4th, under nitrogen guard mode, colostrum is subjected to homogeneous, 80-150bar homogeneous 6 times, 800bar homogeneous 7 times.Cross 3 μ
M filters filter, inflated with nitrogen, embedding.121℃、F0＞ 12 sterilizes.
Embodiment 4
A kind of butyrate clevidipine emulsion, its prescription are as follows：
Wherein refined egg yolk lecithin PC contents are 90%, PE contents are 6%, TC contents are 2%.
Preparation method includes the following steps：
1st, the fresh water for injection of recipe quantity is taken, adds 2% sodium hydroxide to adjust pH value 9.0, adds ethylenediamine tetra-acetic acid
Sodium, glycerine, stir to dissolve uniformly, and nitrogen deoxygenation is passed through in water, and water temperature controls 75 DEG C, adds the refined yolk ovum of recipe quantity
Phosphatide is sheared to refined egg yolk lecithin and is uniformly dispersed, and whole process is completed in nitrogen protection, as water phase.
2nd, take the butyrate clevidipine of recipe quantity, fat oil after 75 DEG C of heating make dissolving, add recipe quantity soybean oil,
Stability, is uniformly mixed, nitrogen filled protection, Oil-temperature control is at 75 DEG C, as oil phase.
3rd, water is mutually while carry out high speed shear, while being slowly injected into oil phase, colostrum is made in shearing, and emulsion temperature is controlled 60
℃。
4th, under nitrogen guard mode, colostrum is subjected to homogeneous, 80-150bar homogeneous 6 times, 800bar homogeneous 7 times.Cross 3 μ
M filters filter, inflated with nitrogen, embedding.121℃、F0＞ 12 sterilizes.
Embodiment 5
A kind of butyrate clevidipine emulsion, its prescription are as follows：
Wherein refined egg yolk lecithin PC contents are 68%, PE contents are 19%, TC contents are 1.5%.
Preparation method includes the following steps：
1st, the fresh water for injection of recipe quantity is taken, adds 2% sodium hydroxide to adjust pH value 9.0, adds ethylenediamine tetra-acetic acid
Sodium, glycerine, stir to dissolve uniformly, and nitrogen deoxygenation is passed through in water, and water temperature controls 75 DEG C, adds the refined yolk ovum of recipe quantity
Phosphatide is sheared to refined egg yolk lecithin and is uniformly dispersed, and whole process is completed in nitrogen protection, as water phase.
2nd, take the butyrate clevidipine of recipe quantity, fat oil after 75 DEG C of heating make dissolving, add recipe quantity soybean oil,
Stability, is uniformly mixed, nitrogen filled protection, Oil-temperature control is at 75 DEG C, as oil phase.
3rd, water is mutually while carry out high speed shear, while being slowly injected into oil phase, colostrum is made in shearing, and emulsion temperature is controlled 60
℃。
4th, under nitrogen guard mode, colostrum is subjected to homogeneous, 80-150bar homogeneous 6 times, 800bar homogeneous 7 times.Cross 3 μ
M filters filter, inflated with nitrogen, embedding.121℃、F0＞ 12 sterilizes.
Embodiment 6
A kind of butyrate clevidipine emulsion, its prescription are as follows：
Wherein refined egg yolk lecithin PC contents are 77%, PE contents are 18%, TC contents are 1.1%.
Preparation method includes the following steps：
1st, the fresh water for injection of recipe quantity is taken, adds 2% sodium hydroxide to adjust pH value 9.0, adds ethylenediamine tetra-acetic acid
Sodium, glycerine, stir to dissolve uniformly, and nitrogen deoxygenation is passed through in water, and water temperature controls 75 DEG C, adds the refined yolk ovum of recipe quantity
Phosphatide is sheared to refined egg yolk lecithin and is uniformly dispersed, and whole process is completed in nitrogen protection, as water phase.
2nd, take the butyrate clevidipine of recipe quantity, fat oil after 75 DEG C of heating make dissolving, add recipe quantity soybean oil,
Stability, is uniformly mixed, nitrogen filled protection, Oil-temperature control is at 75 DEG C, as oil phase.
3rd, water is mutually while carry out high speed shear, while being slowly injected into oil phase, colostrum is made in shearing, and emulsion temperature is controlled 60
℃。
4th, under nitrogen guard mode, colostrum is subjected to homogeneous, 80-150bar homogeneous 6 times, 800bar homogeneous 7 times.Cross 3 μ
M filters filter, inflated with nitrogen, embedding.121℃、F0＞ 12 sterilizes.
Comparative example 1
A kind of butyrate clevidipine emulsion, its prescription are as follows：
Wherein refined egg yolk lecithin PC contents are 92%, PE contents are 4.7%, TC contents are 2.0%.
Preparation method includes the following steps：
1st, the fresh water for injection of recipe quantity is taken, adds 2% sodium hydroxide to adjust pH value 9.0, adds ethylenediamine tetra-acetic acid
Sodium, glycerine, stir to dissolve uniformly, and nitrogen deoxygenation is passed through in water, and water temperature controls 75 DEG C, adds the refined yolk ovum of recipe quantity
Phosphatide is sheared to refined egg yolk lecithin and is uniformly dispersed, and whole process is completed in nitrogen protection, as water phase.
2nd, take the butyrate clevidipine of recipe quantity, fat oil after 75 DEG C of heating make dissolving, add recipe quantity soybean oil,
Stability, is uniformly mixed, nitrogen filled protection, Oil-temperature control is at 75 DEG C, as oil phase.
3rd, water is mutually while carry out high speed shear, while being slowly injected into oil phase, colostrum is made in shearing, and emulsion temperature is controlled 60
℃。
4th, under nitrogen guard mode, colostrum is subjected to homogeneous, 80-150bar homogeneous 6 times, 800bar homogeneous 7 times.Cross 3 μ
M filters filter, inflated with nitrogen, embedding.121℃、F0＞ 12 sterilizes.
Comparative example 2
A kind of butyrate clevidipine emulsion, its prescription are as follows：
Wherein refined egg yolk lecithin PC contents are 64%, PE contents are 20%, TC contents are 0.2%.
Preparation method includes the following steps：
1st, the fresh water for injection of recipe quantity is taken, adds 2% sodium hydroxide to adjust pH value 9.0, adds ethylenediamine tetra-acetic acid
Sodium, glycerine, stir to dissolve uniformly, and nitrogen deoxygenation is passed through in water, and water temperature controls 75 DEG C, adds the refined yolk ovum of recipe quantity
Phosphatide is sheared to refined egg yolk lecithin and is uniformly dispersed, and whole process is completed in nitrogen protection, as water phase.
2nd, take the butyrate clevidipine of recipe quantity, fat oil after 75 DEG C of heating make dissolving, add recipe quantity soybean oil,
Stability, is uniformly mixed, nitrogen filled protection, Oil-temperature control is at 75 DEG C, as oil phase.
3rd, water is mutually while carry out high speed shear, while being slowly injected into oil phase, colostrum is made in shearing, and emulsion temperature is controlled 60
℃。
4th, under nitrogen guard mode, colostrum is subjected to homogeneous, 80-150bar homogeneous 6 times, 800bar homogeneous 7 times.Cross 3 μ
M filters filter, inflated with nitrogen, embedding.121℃、F0＞ 12 sterilizes.
Comparative example 3
A kind of butyrate clevidipine emulsion, its prescription are as follows：
Wherein refined egg yolk lecithin PC contents are 77%, PE contents are 18%, TC contents are 1.1%.
Preparation method includes the following steps：
1st, the fresh water for injection of recipe quantity is taken, adds 2% sodium hydroxide to adjust pH value 9.0, adds ethylenediamine tetra-acetic acid
Sodium, glycerine, stir to dissolve uniformly, and nitrogen deoxygenation is passed through in water, and water temperature controls 75 DEG C, adds the refined yolk ovum of recipe quantity
Phosphatide is sheared to refined egg yolk lecithin and is uniformly dispersed, and whole process is completed in nitrogen protection, as water phase.
2nd, take the butyrate clevidipine of recipe quantity, fat oil after 75 DEG C of heating make dissolving, add recipe quantity soybean oil,
Stability, is uniformly mixed, nitrogen filled protection, Oil-temperature control is at 75 DEG C, as oil phase.
3rd, water is mutually while carry out high speed shear, while being slowly injected into oil phase, colostrum is made in shearing, and emulsion temperature is controlled 60
℃。
4th, under nitrogen guard mode, colostrum is subjected to homogeneous, 800bar homogeneous 7 times.Cross 3 μm of filters to filter, inflated with nitrogen,
Embedding.121℃、F0＞ 12 sterilizes.
Experimental example
Grinding medicine to above example 1-6, comparative example 1-3 and original respectively, (by The Medicines Company, company carries
For lot number：Related experiment 16FE032101) is carried out, the result is shown in table 1 below.
It was found from 1 experimental result of table, butyrate clevidipine emulsion of the invention refines egg yolk lecithin only in prescription
PC contents are in the range of 65-90%, and PE contents are in 5-20%, preferably 10-18% more preferably 12-17%；TC contents are in 0.5-
In the range of 2.0% and homogenizing process uses 40-200bar, and homogeneous 5-6 is after, then with 500-1200bar homogeneous 4-10 times.Ability
Produce more stable sample.
Specific experiment method is as follows：
Milk particle Particle Size Determination Method：This product is taken, according to granularity and determination of particle size distribution (four annex of Chinese Pharmacopoeia 2015 edition
The 3rd methods of IXE), check in accordance with the law, using Mastersizer2000, absorptivity 0.001, index of refraction 1.365, obscurity 5-10%.
More than 5 μm particles are measured according to the light blockage method based on single particle optical sensing technology, and calculating method is overall for the milk particle weighting more than 5 μm
Product accounts for oil phase volume.
Related substance-measuring method：Chromatographic condition, with octadecylsilane chemically bonded silica (Kromasil 100-5C18150 ×
4.6mm) it is filler；With the phosphate aqueous solution (73 of methanol -0.02%：27) it is mobile phase to adjust pH6.0 with triethylamine；Detection
Wavelength is 240nm.Lucifuge operates.Precision, which measures this product 2ml and puts, adds dilution in acetonitrile to be shaken strongly, immediately to scale in 5ml measuring bottles
Filtering, as test solution；Precision measures test solution 1ml, into 100ml measuring bottles, is diluted to scale with mobile phase, shakes
It is even, as contrast solution.20 μ l contrast solutions are taken, inject liquid chromatograph, detection sensitivity is adjusted, makes butyrate clevidipine color
The peak height of spectral peak is about the 20% of full scale, then accurate measurement test solution and each 20 μ l of contrast solution, is injected separately into liquid phase
Chromatograph, 3 times of record chromatogram to principal component peak retention time.If any impurity peaks in test solution chromatogram, calculate most
Big single miscellaneous and total impurities content.
To phase separation, viscosity reduction, precipitation or the preparation of aggregation easily occurs, it is considered as carrying out low temperature or freezing-thawing test.It is low
Temperature experiment and freezing-thawing test should all include circulating three times, and each circulation of low-temperature test is placed 2 days prior to 2~8 DEG C, then 40
DEG C place 2 days, sampling detection.Each circulation of freezing-thawing test is placed 2 days prior to -20~-10 DEG C, then is placed 2 days at 40 DEG C,
Sampling detection.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a kind of preparation method of butyrate clevidipine emulsion, it is characterised in that the butyrate clevidipine emulsion prescription is as follows：
PC contents are 65-90% in the egg yolk lecithin, and PE contents are 5-20%, and TC contents are 0.5-2.0%；
The preparation method of the butyrate clevidipine emulsion includes the following steps：
1) water of recipe quantity is taken, pH value is adjusted to 8~9 with pH adjusting agent, adds edetate, glycerine, stirring makes it
It is uniformly dissolved；Nitrogen deoxygenation is passed through into water, water temperature controls 50~90 DEG C, and the egg yolk lecithin for adding recipe quantity is cut, and is switched to egg
Yellow lecithin is uniformly dispersed；Water phase is made；Whole process carries out under nitrogen protective condition；
2) fat oil of recipe quantity is taken to add butyrate clevidipine, the stabilizer of recipe quantity after 50~90 DEG C of heating make dissolving,
It is uniformly mixed, nitrogen filled protection, system temperature is controlled at 50~90 DEG C, and oil phase is made；
3) gained water is mutually slowly injected into gained oil phase under the conditions of high-speed stirred, colostrum is made in shearing, and emulsion temperature control exists
50~70 DEG C；
4) under nitrogen protective condition, gained colostrum is subjected to twice homogenization, first is inferior to pressure 40-200bar, homogeneous 1-6
Time, second is inferior to pressure 500-1200bar homogeneous 4-10 times；3 μm of filter filterings, inflated with nitrogen, embedding are crossed after homogeneous；Sterilizing；I.e.
Can.
2. preparation method according to claim 1, it is characterised in that first time homogeneous is in pressure 80- in step 4)
150bar, homogeneous 1-6 times；Second homogeneous is equal 4-9 times in pressure 600-1000bar；
Preferably, step 4) first time homogeneous is that second of homogeneous is in pressure 800bar in pressure 80-150bar, homogeneous 6 times
Homogeneous 7 times.
3. preparation method according to claim 1 or 2, it is characterised in that PC contents are 70- in the egg yolk lecithin
85%, PE content are 10-18%, and TC contents are 1.0-2.0%；
Preferably, PC contents are 75-80% in the egg yolk lecithin, and PE contents are 12-17%, and TC contents are 1.5-2.0%.
4. according to claim 1-3 any one of them preparation methods, it is characterised in that the fat oil is soybean oil, middle chain
One or more in triglyceride, peanut oil, olive oil, sesame oil, fish oil, are preferably soybean oil, median chain triglyceride oil
Miscella；And/or
The pH adjusting agent is selected from phosphate, citrate, acetate, borate, hydrochloric acid, phosphoric acid, sodium hydroxide.
5. according to claim 1-4 any one of them preparation methods, it is characterised in that the edetate is second two
One or more in amine tetraacethyl calcium sodium, disodium ethylene diamine tetraacetate.
6. according to claim 1-5 any one of them preparation methods, it is characterised in that the dosage of the edetate
It is preferably 0.005-0.01% for 0.002-0.01%.
7. according to claim 1-6 any one of them preparation methods, it is characterised in that the stabilizer is capric acid or its salt,
Laurate or its salt, myristic acid or its salt, palmitic acid or its salt, palmitoleic acid or its salt, stearic acid or its salt, linoleic acid or
One or more in its salt, leukotrienes or its salt, oleic acid or its salt；Preferably enuatrol or oleic acid, more preferably oleic acid.
8. according to claim 1-7 any one of them preparation methods, it is characterised in that the dosage of the stabilizer is 0.01-
0.06%, it is preferably 0.03-0.06%.
9. the butyrate clevidipine emulsion prepared according to any one of claim 1-8 the method.
10. application of the butyrate clevidipine emulsion on drug for hypertension is prepared described in claim 9.
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| US20130158079A1 (en) * | 2010-10-12 | 2013-06-20 | The Medicines Company | Clevidipine emulsion formulations containing antimicrobial agents |
| CN103479577A (en) * | 2013-09-30 | 2014-01-01 | 山东大学 | Lipid nanosuspension containing clevidipine butyrate, and freeze-drying preparation of lipid nanosuspension |
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| CN104146958A (en) * | 2014-08-26 | 2014-11-19 | 上海信谊药厂有限公司 | Clevidipine butyrate emulsion and preparation method thereof |
| CN105853353A (en) * | 2015-01-20 | 2016-08-17 | 江苏正大丰海制药有限公司 | Method for preparing clevidipine fat emulsion injection |
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| US20130158079A1 (en) * | 2010-10-12 | 2013-06-20 | The Medicines Company | Clevidipine emulsion formulations containing antimicrobial agents |
| CN103479577A (en) * | 2013-09-30 | 2014-01-01 | 山东大学 | Lipid nanosuspension containing clevidipine butyrate, and freeze-drying preparation of lipid nanosuspension |
| CN103736096A (en) * | 2013-12-11 | 2014-04-23 | 李宏 | Composition containing paclitaxel and preparation method thereof |
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Address after: 221200 No. 998, Jiuxu Avenue, Suining Economic Development Zone, Xuzhou City, Jiangsu Province Patentee after: JIANGSU JIUXU PHARMACEUTICAL Co.,Ltd. Patentee after: Li Hong Address before: 221200 No. 66 Qianjin West Road, Suining Economic Development Zone, Xuzhou City, Jiangsu Province Patentee before: JIANGSU JIUXU PHARMACEUTICAL Co.,Ltd. Patentee before: Li Hong |